Heterocyclic aspartyl protease inhibitors

ABSTRACT

Disclosed are compounds of the formula I  
                 
or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein 
         W is a bond, —C(═S)—, —S(O)—, —S(O) 2 —, —C(═O)—, —O—, —C(R 6 )(R 7 )—, —N(R 5 )— or —C(═N(R 5 ))—;    X is —O—, —N(R 5 )— or —C(R 6 )(R 7 )—; provided that when X is —O—, U is not —O—, —S(O)—, —S(O) 2 —, —C(═O)— or —C(═NR 5 )—;    U is a bond, —S(O)—, —S(O) 2 —, —C(O)—, —O—, —P(O)(OR 15 )—, —C(═NR 5 )—, —(C(R 6 )(R 7 )) b — or —N(R 5 )—; wherein b is 1 or 2; provided that when W is —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—, U is not —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—; provided that when X is —N(R 5 )— and W is —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—, then U is not a bond;    and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I. Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes.        

     Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic m 1  agonist or m 2  antagonist.

REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Ser. No. 11/010,772 filed onDec. 13, 2004, which claims the benefit of U.S. Provisional ApplicationNo. 60/529,535 filed Dec. 15, 2003.

FIELD OF THE INVENTION

This invention relates to heterocyclic aspartyl protease inhibitors,pharmaceutical compositions comprising said compounds, their use in thetreatment of cardiovascular diseases, cognitive and neurodegenerativediseases, and their use as inhibitors of the Human ImmunodeficiencyVirus, plasmepsins, cathepsin D and protozoal enzymes.

BCKGROUND

Eight human aspartic proteases of the A1 (pepsin-like) family are knownto date: pepsin A and C, renin, BACE, BACE 2, Napsin A, cathepsin D inpathological conditions.

The role of renin-angiotensin system (RAS) in regulation of bloodpressure and fluid electrolyte has been well established (Oparil, S, etal. N Engl J Med 1974; 291:381-401/446-57). The octapeptideAngiotensin-II, a potent vasoconstrictor and stimulator for release ofadrenal aldosterone, was processed from the precursor decapeptideAngiotensin-I, which in turn was processed from angiotensinogen by therenin enzyme. Angiotensin-II was also found to play roles in vascularsmooth muscle cell growth, inflammation, reactive oxygen speciesgeneration and thrombosis, influence atherogenesis and vascular damage.Clinically, the benefit of interruption of the generation ofangiotensin-II through antagonism of conversion of angiotensin-I hasbeen well known and there are a number of ACE inhibitor drugs on themarket. The blockade of the earlier conversion of angiotensinogen toangiotensin-I, i.e. the inhibition of renin enzyme, is expected to havesimilar but not identical effects. Since renin is an aspartyl proteasewhose only natural substrate is angiotensinogen, it is believed thatthere would be less frequent adverse effect for controlling high bloodpressure and related symptoms regulated by angiotensin-II through itsinhibition.

Another protease, Cathepsin-D, is involved in lysosomal biogenesis andprotein targeting, and may also be involved in antigen processing andpresentation of peptide fragments. It has been linked to numerousdiseases including, Alzheimer's, disease, connective tissue disease,muscular dystrophy and breast cancer.

Alzheimer's disease (AD) is a progressive neurodegenerative disease thatis ultimately fatal. Disease progression is associated with gradual lossof cognitive function related to memory, reasoning, orientation andjudgment. Behavioral changes including confusion, depression andaggression also manifest as the disease progresses. The cognitive andbehavioral dysfunction is believed to result from altered neuronalfunction and neuronal loss in the hippocampus and cerebral cortex. Thecurrently available AD treatments are palliative, and while theyameliorate the cognitive and behavioral disorders, they do not preventdisease progression. Therefore there is an unmet medical need for ADtreatments that halt disease progression.

Pathological hallmarks of AD are the deposition of extracellularβ-amyloid (Aβ) plaques and intracellular neurofibrillary tanglescomprised of abnormally phosphorylated protein tau. Individuals with ADexhibit characteristic Aβ deposits, in brain regions known to beimportant for memory and cognition. It is believed that Aβ is thefundamental causative agent of neuronal cell loss and dysfunction whichis associated with cognitive and behavioral decline. Amyloid plaquesconsist predominantly of Aβ peptides comprised of 40-42 amino acidresidues, which are derived from processing of amyloid precursor protein(APP). APP is processed by multiple distinct protease activities. Aβpeptides result from the cleavage of APP by β-secretase at the positioncorresponding to the N-terminus of Aβ, and at the C-terminus byγ-secretase activity. APP is also cleaved by α-secretase activityresulting in the secreted, non-amyloidogenic fragment known as solubleAPP.

An aspartyl protease known as BACE-1 has been identified as theβ-secretase activity responsible for cleavage of APP at the positioncorresponding to the N-terminus of Aβ peptides.

Accumulated biochemical and genetic evidence supports a central role ofAβ in the etiology of AD. For example, Aβ has been shown to be toxic toneuronal cells in vitro and when injected into rodent brains.Furthermore inherited forms of early-onset AD are known in whichwell-defined mutations of APP or the presenilins are present. Thesemutations enhance the production of Aβ and are considered causative ofAD.

Since Aβ peptides are formed as a result β-secretase activity,inhibition of BACE-1 should inhibit formation of Aβ peptides. Thusinhibition of BACE-1 is a therapeutic approach to the treatment of ADand other cognitive and neurodegenerative diseases caused by Aβ plaquedeposition.

Human immunodeficiency virus (HIV), is the causative agent of acquiredimmune deficiency syndrome (AIDS). It has been clinically demonstratedthat compounds such as indinavir, ritonavir and saquinavir which areinhibitors of the HIV aspartyl protease result in lowering of viralload. As such, the compounds described herein would be expected to beuseful for the treatment of AIDS. Traditionally, a major target forresearchers has been HIV-1 protease, an aspartyl protease related torenin.

In addition, Human T-cell leukemia virus type I (HTLV-I) is a humanretrovirus that has been clinically associated with adult T-cellleukemia and other chronic diseases. Like other retroviruses, HTLV-Irequires an aspartyl protease to process viral precursor proteins, whichproduce mature virions. This makes the protease an attractive target forinhibitor design. (Moore, et al. Purification of HTLV-I Protease andSynthesis of Inhibitors for the treatment of HTLV-I Infection 55^(th)Southeast Regional Meeting of the American Chemical Society, Atlanta,Ga., US Nov. 16-19, 2003 (2003), 1073. CODEN; 69EUCH Conference, AN2004:137641 CAPLUS.)

Plasmepsins are essential aspartyl protease enzymes of the malarialparasite. Compounds for the inhibition of aspartyl proteasesplasmepsins, particularly I, II, IV and HAP, are in development for thetreatment of malaria. (Freire, et al. WO 2002074719. Na Byoung-Kuk, etal. Aspartic proteases of Plasmodium vivax are highly conserved in wildisolates Korean Journal of Prasitology (2004 June), 42(2) 61-6. Journalcode: 9435800) Furthermore, compounds used to target aspartyl proteasesplasmepsins (e.g. I, II, IV and HAP), have been used to kill malarialparasites, thus treating patients thus afflicted.

SUMMARY OF THE INVENTION

The present invention relates to compounds having the structural formulaI

or a stereoisomer, tautomer, or pharmaceutically acceptable salt orsolvate thereof, wherein

W is a bond, —C(═S)—, —S(O)—, —S(O)₂—, —C(═O)—, —O—, —C(R⁶)(R⁷)—,—N(R⁵)— or —C(═N(R⁵))_;

X is —O—, —N(R⁵)— or —C(R⁶)(R⁷)—; provided that when X is —O—, U is not—O—, —S(O)—, —S(O)₂—, —C(═O)— or —C(═NR⁵)—;

U is a bond, —S(O)—, —S(O)₂—, —C(O)—, —O—, —P(O)(OR¹⁵)—, —C(═NR⁵)—,—(C(R⁶)(R⁷))_(b)— or —N(R⁵)—; wherein b is 1 or 2; provided that when Wis —S(O)—, —S(O)₂—, —O—, or —N(R⁵)—, U is not —S(O)—, —S(O)₂—, —O—, or—N(R⁵)—; provided that when X is —N(R⁵)— and W is —S(O)—, —S(O)₂—, —O—,or —N(R⁵)—, then U is not a bond;

R¹, R² and R⁵ are independently selected from the group consisting of H,alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, —OR¹⁵, —CN, —C(O)R⁸, —C(O)OR⁹, —S(O)R¹⁰, —S(O)₂R¹⁰,—C(O)N(R¹¹)(R¹²), —S(O)N(R¹¹)(R¹²), —S(O)₂N(R¹¹)(R¹²), —NO₂, —N═C(R⁸)₂and —N(R⁸)₂, provided that R¹ and R⁵ are not both selected from —NO₂,—N═C(R⁸)₂ and —N(R⁸)₂;

R³, R⁴, R⁶ and R⁷ are independently selected from the group consistingof H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,halo, —CH₂—O—Si(R⁹)(R¹⁰)(R¹⁹), —SH, —CN, —OR⁹, —C(O)R⁸, —C(O)OR⁹,—C(O)N(R¹)(R¹²), —SR¹⁹, —S(O)N(R¹¹)(R¹²), —S(O)₂N(R¹¹)(R¹²),—N(R¹¹)(R¹²), —N(R¹¹)C(O)R⁸, —N(R¹¹)S(O)R¹⁰, —N(R¹¹)C(O)N(R¹²)(R¹³),—N(R¹)C(O)OR⁹ and —C(═NOH)R⁸; provided that when U is —O— or —N(R⁵)—,then R³, R⁴, R⁶ and R⁷ are not halo, —SH, —OR⁹, —SR¹⁹, —S(O)N(R¹)(R¹²),—S(O)₂N(R¹¹)(R¹²), —N(R¹)(R¹²), —N(R¹¹)C(O)R⁸, —N(R¹¹)S(O)R¹⁰,—N(R¹¹)C(O)N(R¹²)(R¹³), or —N(R¹¹)C(O)OR⁹; provided that when W is —O—or —N(R⁵)—, then R³ and R⁴ are not halo, —SH, —OR⁹, —SR¹⁹,—S(O)N(R¹¹)(R¹²), —S(O)₂N(R¹¹)(R¹²), —N(R¹¹)(R¹²), —N(R¹¹)C(O)R⁸,—N(R¹¹)S(O)R¹⁰, —N(R¹¹)C(O)N(R¹²)(R¹³), or —N(R¹¹)C(O)OR⁹; and providedthat when X is —N(R⁵)—, W is —C(O)— and U is a bond; —R³ and R⁴ are nothalo, —CN, —SH, —OR⁹, —SR¹⁹, —S(O)N(R¹¹)(R¹²) or —S(O)₂N(R¹¹)(R¹²); orR³, R⁴, R⁶ and R⁷, together with the carbon to which they are attached,form a 3-7 membered cycloalkyl group optionally substituted by R¹⁴ or a3-7 membered cycloalkylether optionally substituted by R¹⁴;

or R³ and R⁴ or R⁶ and R⁷ together with the carbon to which they areattached, are combined to form multicyclic groups such as

wherein M is —CH₂—, S, —N(R¹⁹)— or 0, A and B are independently aryl orheteroaryl and q is 0, 1 or 2 provided that when q is 2, one M must be acarbon atom and when q is 2, M is optionally a double bond; and with theproviso that when R³, R⁴, R⁶ and R⁷ form said multicyclic groups

then adjacent R³ and R⁴ or R⁶ and R⁷ groups cannot be combined to formsaid multicyclic groups;

R⁸ is independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, —OR¹⁵, —N(R¹⁵) (R¹⁶), —N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷),—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and —N(R¹⁵)C(O)OR¹⁶;

R⁹ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, arylalkyl, heteroaryl and heteroarylalkyl;

R¹⁰ is independently selected from the group consisting of H, alkyl,alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and—N(R¹⁵) (R¹⁶);

R¹¹, R¹² and R¹³ are independently selected from the group consisting ofH, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,—C(O)R⁸, —C(O)OR⁹, —S(O)R¹⁰, —S(O)₂R¹⁰, —C(O)N(R¹⁵)(R¹⁶),—S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶) and —CN;

R¹⁴ is 1-5 substituents independently selected from the group consistingof alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁵),—C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶,—N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and —N(R¹⁵)C(O)OR¹⁶;

R¹⁵, R¹⁶ and R¹⁷ are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R¹⁸-alkyl,R¹⁸-cycloalkyl, R¹⁸-cycloalkylalkyl, R¹⁸-heterocycloalkyl,R¹⁸-heterocycloalkylalkyl, R¹⁸-aryl, R⁸-arylalkyl, R¹⁸-heteroaryl andR¹⁸-heteroarylalkyl; or

R¹⁵, R¹⁶ and R¹⁷ are

wherein R²³ numbers 0 to 5 substituents, m is 0 to 6 and n is 1 to 5;

R¹⁸ is 1-5 substituents independently selected from the group consistingof alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO₂,halo, heteroaryl, HO-alkyoxyalkyl, —CF₃, —CN, alkyl-CN, —C(O)R¹⁹,—C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂,—C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)₂R²⁰,—S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl),—S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

or two R¹⁸ moieties on adjacent carbons can be linked together to form

R¹⁹ is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R²⁰ is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl,heteroaryl or heteroarylalkyl;

and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkenyl and alkynyl groups in R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are independently unsubstitutedor substituted by 1 to 5 R²¹ groups independently selected from thegroup consisting of alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR¹⁵,—C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(R¹⁵) (OR¹⁶),—N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, ═NOR¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵; and wherein each of thealkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkenyl and alkynyl groups in R²¹ are independently unsubstituted orsubstituted by 1 to 5 R²² groups independently selected from the groupconsisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl,heteroaryl, halo, —CF₃, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,-alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(R¹⁶), —N(R¹⁵) (R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷); —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃,═NOR¹⁵, —NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵;

or two R²¹ or two R²² moieties on adjacent carbons can be linkedtogether to form

and when R²¹ or R²² are selected from the group consisting of—C(═NOR¹⁵)R¹⁶, —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶) (R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶ and —CH₂—N(R¹⁵)C(O)OR¹⁶, R¹⁵and R¹⁶ together can be a C₂ to C₄ chain wherein, optionally, one, twoor three ring carbons can be replaced by —C(O)— or —N(H)— and R¹⁵ andR¹⁶, together with the atoms to which they are attached, form a 5 to 7membered ring, optionally substituted by R²³;

R²³ is 1 to 5 groups independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴,—C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵),—C(═NOR²⁴)R²⁵—P(O)(OR²⁴)(R²⁵)—N(R²⁴)(R²⁵)-alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵—CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)₂R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴; and wherein each of thealkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkenyl and alkynyl groups in R²³ are independently unsubstituted orsubstituted by 1 to 5 R²⁷ groups independently selected from the groupconsisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,halo, —CF₃, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴, alkyl-C(O)OR²⁴, C(O)N(R²⁴)(R²⁵)—SR²⁴—S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵),(═NOR²⁴)R²⁵—P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)₂R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴;

R²⁴, R²⁵ and R²⁶ are independently selected from the group consisting ofH, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, R²⁷-alkyl, R²⁷-cycloalkyl, R²⁷-cycloalkylalkyl,R²⁷-heterocycloalkyl, R²⁷-heterocycloalkylalkyl, R²⁷-aryl,R²⁷-arylalkyl, R²⁷-heteroaryl and R²⁷-heteroarylalkyl;

R²⁷ is 1-5 substituents independently selected from the group consistingof alkyl, aryl, arylalkyl, —NO₂, halo, —CF₃, —CN, alkyl-CN, —C(O)R²⁸,—C(O)OH, —C(O)OR²⁸, —C(O)NHR²⁹, —C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl),—C(O)N(alkyl)(heteroaryl), —SR²⁸, —S(O)₂R²⁹, —S(O)NH₂, —S(O)NH(alkyl),—S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NH R²⁸,—S(O)₂NH(aryl), —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OH, —OR²⁹, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁹, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R²⁹, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁹, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

R²⁸ is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and

R²⁹ is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl;

provided that when W is —C(O)— and U is a bond, R¹ is not optionallysubstituted phenyl, and that when U is —C(O)— and W is a bond, R⁵ is notoptionally substituted phenyl;

provided that neither R¹ nor R⁵ is —C(O)-alkyl-azetidinone or alkyldi-substituted with (—COOR¹⁵ or —C(O)N(R¹⁵)(R¹⁶)) and (—N(R¹⁵)(R¹⁶),—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶,—N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷)or —N(R¹⁵)C(O)OR¹⁶);

provided that when R¹ is methyl, X is —N(R⁵)—, R² is H, W is —C(O)— andU is a bond, (R³, R⁴) is not (H, H), (phenyl, phenyl), (H, phenyl),(benzyl, H), (benzyl, phenyl), (i-butyl, H), (i-butyl, phenyl),(OH-phenyl, phenyl), (halo-phenyl, phenyl), or (CH₃O-phenyl,NO₂-phenyl); and when W is a bond and U is —C(O)—, (R³, R⁴) is not (H,H), (phenyl, phenyl), (H, phenyl), (benzyl, H), (benzyl, phenyl),(i-butyl, H), (i-butyl, phenyl), (OH-phenyl, phenyl), (halo-phenyl,phenyl), or (CH₃O-phenyl, NO₂-phenyl);

provided that when X is —N(R⁵)—, R¹ and R⁵ are each H, W is C(O)— and Uis a bond, (R³, R⁴) is not (optionally substituted phenyl, optionallysubstituted benzyl), (optionally substituted phenyl, heteroarylalkyl) or(heteroaryl, heteroarylalkyl);

provided that when U is a bond, W is —C(O)—, and R³ and R⁴ form a ringwith the carbon to which they are attached, R¹ is not 2-CF₃-3-CN-phenyl;

provided that when X is —N(R⁵)—, U is —O— and W is a bond or—C(R⁶)(R⁷)—, (R³, R⁴) is not (H, —NHC(O)-alkyl-heteroaryl) or (H,alkyl-NHC(O)-alkyl-heteroaryl); and

provided that when X is —N(R⁵)—, R¹ and R⁵ are not-alkylaryl-aryl-SO₂—N(R¹⁵)(R¹⁶) wherein R¹⁵ is H and R¹⁶ is heteroaryl;

provided that when R¹ is R²¹-aryl or R²¹-arylalkyl, wherein R²¹ is—OCF₃, —S(O)CF₃, —S(O)₂CF₃, —S(O)alkyl, —S(O)₂alkyl, —S(O)₂CHF₂,—S(O)₂CF₂CF₃, —OCF²CHF₂, —OCHF₂, —OCH₂CF₃, —SF₅ or —S(O)₂NR¹⁵R¹⁶;

wherein R¹⁵ and R¹⁶ are independently selected from the group consistingof H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,R¹⁸-alkyl, R¹⁸-cycloalkyl, R¹⁸-heterocycloalkyl, R¹⁸-aryl andR¹⁸-heteroaryl; U is a bond or —CH₂; and X is —N(R⁵)—; then R⁵ is H;

provided that when U is a bond,

R³ and R⁴ are alkyl,

where R²¹ is halo, —CN, alkyl, alkoxy, haloalkyl or haloalkoxy, or R³and R⁴, together with the carbon to which they are attached, form a 3-7membered cycloalkyl group,

and R¹ is

where a is 0 to 6 and R²² is alkyl, alkoxy, halo, —CN, —OH, —NO₂ orhaloalkyl;

then R^(21a) is not H, —C(O)₂R¹⁵, wherein R¹⁵ is selected from the groupconsisting of alkyl, cycloalkyl and alkyl substituted with phenyl, alkylor alkyl-R²² wherein R²² is selected from the group consisting of

phenyl,

phenyl substituted with alkyl, and

wherein R²² is selected from the group consisting of H, methoxy, nitro,oxo, —OH, halo and alkyl,

In another aspect, the invention relates to a pharmaceutical compositioncomprising at least one compound of formula I and a pharmaceuticallyacceptable carrier.

In another aspect, the invention comprises the method of inhibitingaspartyl protease comprising administering at least one compound offormula I to a patient in need of such treatment.

More specifically, the invention comprises: the method of treating acardiovascular disease such as hypertension, renal failure, or a diseasemodulated by renin inhibition; the method of treating HumanImmunodeficiency Virus; the method of treating a cognitive orneurodegenerative disease such as Alzheimer's Disease; the method ofinhibiting plasmepins I and II for treatment of malaria; the method ofinhibiting Cathepsin D for the treatment of Alzheimer's Disease, breastcancer, and ovarian cancer; and the method of inhibiting protozoalenzymes, for example inhibition of plasmodium falciparnum, for thetreatment of fungal infections. Said method of treatment compriseadministering at least one compound of formula I to a patient in need ofsuch treatment. In particular, the invention comprises the method oftreating Alzheimer's disease comprising administering at least onecompound of formula I to a patient in need of such treatment.

In another aspect, the invention comprises the method of treatingAlzheimer's disease comprising administering to a patient I need of suchtreatment a combination of at least one compound of formula I and acholinesterase inhibitor or a muscarinic m₁ agonist or m₂ antagonist.

In a final aspect, the invention relates to a kit comprising in separatecontainers in a single package pharmaceutical compositions for use incombination, in which one container comprises a compound of formula I ina pharmaceutically acceptable carrier and a second container comprises acholinesterase inhibitor or a muscarinic m₁ agonist or m₂ antagonist ina pharmaceutically acceptable carrier, the combined quantities being aneffective amount to treat a cognitive disease or neurodegenerativedisease such as Alzheimer's disease.

DETAILED DESCRIPTION

Compounds of formula I wherein X, W and U are as defined above includethe following independently preferred structures:

In compounds of formulas IA to IF, U is preferably a bond or—C(R⁶)(R⁷)—. In compounds of formula IG and IH, U is preferably —C(O)—.

It will be understood that since the definition of R¹ is the same as thedefinition of R⁵, when X is —N(R⁵)—, compounds of formula I wherein W isa bond and U is a bond, —S(O)—, —S(O)₂—, —C(O)—, —O—, —C(R⁶)(R⁷)— or—N(R⁵)— are equivalent to compounds of formula I wherein U is a bond andW is a bond, —S(O)—, —S(O)₂—, —C(O)—, —O—, —C(R⁶)(R⁷)— or —N(R⁵)—.

More preferred compounds of the invention are those of formula IBwherein U is a bond or those of formula IB wherein U is —C(R⁶)(R⁷)—.

Another group of preferred compounds of formula I is that wherein R² isH.

R³, R⁴, R⁶ and R⁷ are preferably selected from the group consisting ofalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,halo, —CH₂—O—Si(R⁹)(R¹⁰)(R¹⁹), —SH, —CN, —OR⁹, —C(O)R⁸, —C(O)OR⁹,—C(O)N(R¹¹)(R¹²), —SR¹⁹, —S(O)N(R¹¹)(R¹²), —S(O)₂N(R¹¹)(R¹²),—N(R¹¹)(R¹²), —N(R¹¹)C(O)R⁸, —N(R¹¹)S(O)R¹⁰, —N(R¹¹)C(O)N(R¹²)(R¹³),—N(R¹¹)C(O)OR⁹ and —C(═NOH)R⁸.

R³, R⁴, R⁶ and R⁷ are preferably selected from the group consisting ofaryl, heteroaryl, heteroarylalkyl, arylalkyl, cycloalkyl,heterocycloalkyl, heterocycloalkylalkyl, alkyl and cycloalkylalkyl.

In a group of preferred compounds

U is a bond or —C(O)—;

W is a bond or —C(O)—;

X is —N(R⁵);

R¹ is H, alkyl, R²¹-alkyl, arylalkyl, R²¹-arylalkyl, cycloalkylalkyl,R²¹-cycloalkylalkyl, heterocycloalkyalkyl or R²¹-heterocycloalkylalkyl,

R² is H;

R³ is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R²¹-alkyl,R²¹-cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl or R²¹-arylalkyl;

R⁴ is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R²¹-alkyl,R²¹-cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl or R²¹-arylalkyl;

R⁵ is H, alkyl, R²¹-alkyl, arylalkyl, R²¹-arylalkyl, cycloalkylalkyl,R²¹-cycloalkylalkyl, heterocycloalkyalkyl or R²¹-heterocycloalkylalkyl;

R⁶ is alkyl cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R²¹-alkyl,R²¹-cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl or R²¹-arylalkyl;

R⁷ is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R²¹-alkyl,R²¹-cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl or R²¹-arylalkyl;

R¹⁵, R¹⁶ and R¹⁷ is H, R¹⁸-alkyl, alkyl or

R²¹ is alkyl, aryl, halo, —OR¹⁵, —NO₂, —C(O)R¹⁵,—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) or —CH(R¹⁵)(R¹⁶);

n is 1;

m is 1;

R¹ is —OR²⁰

R²⁰ is aryl; and

R²³ is alkyl.

In a group of preferred compounds

R³, R⁴, R⁶ and R⁷ are

and R¹ and R⁵ is H, CH₃,

In an additional group of preferred compounds;

U is a bond or —C(O)—;

W is a bond or —C(O)—;

X is —N(R⁵)—;

R¹ is H, alkyl, R²¹-alkyl, arylalkyl, R²¹-arylalkyl, cycloalkylalkyl,R²¹-cycloalkylalkyl, heterocycloalkyalkyl or R²¹-heterocycloalkylalkyl,

R² is H;

R³ is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R²¹-alkyl,R²¹-cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl, R²¹-arylalkyl,heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl,R²¹-heteroarylalkyl, R²¹-heteroaryl, R²¹-heterocycloalkyl orR²¹-heterocycloalkylalkyl;

R⁴ is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R²¹-alkyl,R²¹-cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl, R²¹-arylalkyl,heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl,R²¹-heteroarylalkyl, R²¹-heteroaryl, R²¹-heterocycloalkyl orR²¹-heterocycloalkylalkyl;

R⁵ is H, alkyl, R²¹-alkyl, arylalkyl, R²¹-arylalkyl, cycloalkylalkyl,R²¹-cycloalkylalkyl, heterocycloalkyalkyl or R²¹-heterocycloalkylalkyl;

R⁶ is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R²¹-alkyl,R²¹ cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl, R²¹-arylalkyl,heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl,R²¹-heteroarylalkyl, R²¹-heteroaryl, R²¹-heterocycloalkyl orR²¹-heterocycloalkylalkyl;

R⁷ is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R²¹-alkyl,R²¹-cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl, R²¹-arylalkyl,heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl,R²¹-heteroarylalkyl, R²¹-heteroaryl, R²¹-heterocycloalkyl orR²¹-heterocycloalkylalkyl;

R¹⁵, R¹⁶ and R¹⁷ is H, cycloalkyl, cycloalkylalkyl, R¹⁸-alkyl, alkyl,aryl, R¹⁸-aryl, R¹⁸-arylalkyl, arylalkyl,

n is 1 or 2;

m is 0 or 1;

R¹⁸ is —OR²⁰ or halo;

R²⁰ is aryl or halo substituted aryl;

R²¹ is alkyl, aryl, heteroaryl, R²²-alkyl, R²²-aryl, R²²-heteroaryl,halo, heterocycloalkyl, —N(R¹⁵)(R¹⁶), —OR¹⁵, —NO₂, —C(O)R¹⁵,—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)₂R¹, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) or —CH(R¹⁵)(R¹⁶);

R²² is —OR¹⁵ or halo and

R²³ is H or alkyl.

It is noted that the carbons of formula I may be replaced with 1 to 3silicon atoms so long as all valency requirements are satisfied.

As used above, and throughout the specification, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. Non-limiting examples ofsuitable alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, n-pentyl, heptyl, nonyl and decyl. R²-substitutedalkyl groups include fluoromethyl, trifluoromethyl andcyclopropylmethyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkenyl groups includeethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyland decenyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more substituents (e.g., R¹⁸, R²¹, R²², etc.) which may be the sameor different, and are as defined herein or two substituents on adjacentcarbons can be linked together to form

Non-limiting examples of suitable aryl groups include phenyl andnaphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one to eight of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more R²¹substituents which may be the same or different, and are as definedherein. The prefix aza, oxa or thia before the heteroaryl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively, ispresent as a ring atom. A nitrogen atom of a heteroaryl can beoptionally oxidized to the corresponding N-oxide. Non-limiting examplesof suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl,furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl,pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore R²¹ substituents which may be the same or different, and are asdefined above. Non-limiting examples of suitable monocyclic cycloalkylsinclude cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.Non-limiting examples of suitable multicyclic cycloalkyls include1-decalin, norbornyl, adamantyl and the like. Further non-limitingexamples of cycloalkyl include the following

“Cycloalkylether” means a non-aromatic ring of 3 to 7 members comprisingan oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can besubstituted, provided that substituents adjacent to the ring oxygen donot include halo or substituents joined to the ring through an oxygen,nitrogen or sulfur atom.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.The cycloalkenyl ring can be optionally substituted with one or more R²¹substituents which may be the same or different, and are as definedabove. Preferred cycloalkenyl rings contain about 5 to about 7 ringatoms. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising about 3 to about 14 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur atom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.The prefix aza, oxa or thia before the heterocyclenyl root name meansthat at least a nitrogen, oxygen or sulfur atom respectively is presentas a ring atom. The heterocyclenyl can be optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined above. The nitrogen or sulfur atom of the heterocyclenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclicazaheterocyclenyl groups include 1,2,3,4-tetrahydropyridine,1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine,1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limiting examples ofsuitable oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran,dihydrofuranyl, fluorodihydrofuranyl, and the like. Non-limiting exampleof a suitable multicyclic oxaheterocyclenyl group is7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitablemonocyclic thiaheterocyclenyl rings include dihydrothiophenyl,dihydrothiopyranyl, and the like.

“Halo” means fluoro, chloro, bromo, or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl is replaced by a halo group defined above.

“Heterocyclyl” (or heterocycloalkyl) means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 14ring atoms, preferably about 5 to about 10 ring atoms, in which 1-3,preferably 1 or 2 of the atoms in the ring system is an element otherthan carbon, for example nitrogen, oxygen or sulfur, alone or incombination. There are no adjacent oxygen and/or sulfur atoms present inthe ring system. Preferred heterocyclyls contain about 5 to about 6 ringatoms. The prefix aza, oxa or thia before the heterocyclyl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively ispresent as a ring atom. The heterocyclyl can be optionally substitutedby one or more R²¹ substituents which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and thelike.

“Arylalkyl” means an aryl-alkyl-group in which the aryl and alkyl are aspreviously described. Preferred aralkyls comprise a lower alkyl group.Non-limiting examples of suitable aralkyl groups include benzyl,2-phenethyl and naphthalenylmethyl. The bond to the parent moiety isthrough the alkyl.

“Arylcycloalkyl” means a group derived from a fused aryl and cycloalkylas defined herein. Preferred arylcycloalkyls are those wherein aryl isphenyl and cycloalkyl consists of about 5 to about 6 ring atoms. Thearylcycloalkyl can be optionally substituted by 1-5 R²¹ substituents.Non-limiting examples of suitable arylcycloalkyls include indanyl and1,2,3,4-tetrahydronaphthyl and the like. The bond to the parent moietyis through a non-aromatic carbon atom.

“Arylheterocycloalkyl” means a group derived from a fused aryl andheterocycloalkyl as defined herein. Preferred arylcycloalkyls are thosewherein aryl is phenyl and heterocycloalkyl consists of about 5 to about6 ring atoms. The arylheterocycloalkyl can be optionally substituted by1-5 R²¹ substituents. Non-limiting examples of suitablearylheterocycloalkyls include

The bond to the parent moiety is through a non-aromatic carbon atom.

Similarly, “heteroarylalkyl” “cycloalkylalkyl” and“heterocycloalkylalkyl” mean a heteroaryl-, cycloalkyl- orheterocycloalkyl-alkyl-group in which the heteroaryl, cycloalkyl,heterocycloalkyl and alkyl are as previously described. Preferred groupscontain a lower alkyl group. The bond to the parent moiety is throughthe alkyl.

“Acyl” means an H—C(O)—, alkyl-C(O)—, alkenyl-C(O)—, alkynyl-C(O)— orcycloalkyl-C(O)— group in which the various groups are as previouslydescribed. The bond to the parent moiety is through the carbonyl.Preferred acyls contain a lower alkyl. Non-limiting examples of suitableacyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl,butanoyl and cyclohexanoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.The bond to the parent moiety is through the ether oxygen.

“Alkyoxyalkyl” means a group derived from an alkoxy and alkyl as definedherein. The bond to the parent moiety is through the alkyl.

“Arylalkenyl” means a group derived from an aryl and alkenyl as definedherein. Preferred arylalkenyls are those wherein aryl is phenyl and thealkenyl consists of about 3 to about 6 atoms. The arylalkenyl can beoptionally substituted by one or more R²⁷ substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

“Arylalkynyl” means a group derived from a aryl and alkynyl as definedherein. Preferred arylalkynyls are those wherein aryl is phenyl and thealkynyl consists of about 3 to about 6 atoms. The arylalkynyl can beoptionally substituted by one or more R²⁷ substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

The suffix “ene” on alkyl, aryl, hetercycloalkyl, etc. indicates adivalent moiety, e.g., —CH₂CH₂— is ethylene, and

is para-phenylene.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties, in available position orpositions.

Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, orheteroarylalkyl moiety includes substitution on the ring portion and/oron the alkyl portion of the group.

When a variable appears more than once in a group, e.g., R⁸ in —N(R⁸)₂,or a variable appears more than once in the structure of formula I,e.g., R¹⁵ may appear in both R¹ and R³, the variables can be the same ordifferent.

With reference to the number of moieties (e.g., substituents, groups orrings) in a compound, unless otherwise defined, the phrases “one ormore” and “at least one” mean that there can be as many moieties aschemically permitted, and the determination of the maximum number ofsuch moieties is well within the knowledge of those skilled in the art.With respect to the compositions and methods comprising the use of “atleast one compound of formula I,” one to three compounds of formula Ican be administered at the same time, preferably one.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The wavy line

as a bond generally indicates a mixture of, or either of, the possibleisomers, e.g., containing (R)- and (S)-stereochemistry. For example,

means containing both

Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring carbon atoms.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

represents

It should also be noted that any heteroatom with unsatisfied valences inthe text, schemes, examples, structural formulae, and any Tables hereinis assumed to have the hydrogen atom or atoms to satisfy the valences.

Those skilled in the art will recognize that certain compounds offormula I are tautomeric, and all such tautomeric forms are contemplatedherein as part of the present invention. For example, a compound whereinX is —N(R⁵)— and R¹ and R⁵ are each H can be represented by any of thefollowing structures:

When R²¹ and R²², are, for example, —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and R¹⁵ andR¹⁶ form a ring, the moiety formed, is, for example,

or

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of formula I or a salt and/or solvatethereof. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press, both of which are incorporated herein by referencethereto.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting aspartyl protease and/or inhibiting BACE-1 andthus producing the desired therapeutic effect in a suitable patient.

The compounds of formula I form salts which are also within the scope ofthis invention. Reference to a compound of formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the formula I may be formed, for example, by reacting a compound offormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization. Acids (and bases) which are generallyconsidered suitable for the formation of pharmaceutically useful saltsfrom basic (or acidic) pharmaceutical compounds are discussed, forexample, by S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website); and P. HeinrichStahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (2002) Int'l. Union of Pure and AppliedChemistry, pp. 330-331. These disclosures are incorporated herein byreference thereto.

Exemplary acid addition salts include acetates, adipates, alginates,ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides,hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates,methanesulfonates, methyl sulfates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, sulfates, sulfonates (such as those mentionedherein), tartarates, thiocyanates, toluenesulfonates (also known astosylates,) undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, aluminum salts, zinc salts, salts withorganic bases (for example, organic amines) such as benzathines,diethylamine, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, piperazine,phenylcyclohexylamine, choline, tromethamine, and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quarternized with agents such as lower alkyl halides (e.g.methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates),long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons on various substituents, including enantiomeric forms (which mayexist even in the absence of asymmetric carbons), rotameric forms,atropisomers, and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers,or may be admixed, for example, as racemates or with all other, or otherselected, stereoisomers. The chiral centers of the present invention canhave the S or R configuration as defined by the IUPAC 1974Recommendations. The use of the terms “salt”, “solvate” “prodrug” andthe like, is intended to equally apply to the salt, solvate and prodrugof enantiomers, stereoisomers, rotamers, tautomers, racemates orprodrugs of the inventive compounds.

Polymorphic forms of the compounds of formula I, and of the salts,solvates and prodrugs of the compounds of formula I, are intended to beincluded in the present invention

Compounds of formula I can be made using procedures known in the art.Preparative methods for preparing starting materials and compounds offormula I are show below as general reaction schemes (Method A, MethodB, etc.) followed by specific procedures, but those skilled in the artwill recognize that other procedures can also be suitable. In theSchemes and in the Examples below, the following abbreviations are used:

methyl: Me; ethyl: Et; propyl: Pr; butyl: Bu; benzyl: Bn; tertiarybutyloxycarbonyl: Boc or BOC

high pressure liquid chromatography: HPLC

liquid chromatography mass spectroscopy: LCMS

room temperature: RT or rt

day: d; hour: h; minute: min

retention time: Rt

microwave: gW

saturated: sat.; anhydrous: anhyd.

1-hydroxybenzotriazole: HOBt

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: EDCI

ethyl acetate: EtOAc

Benzyloxycarbonyl: CBZ

[1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate)]: Selectfluor

1,8-diazabicyclo[5,4,0]undec-7-ene: DBU

tetrahydrofuran: THF; N,N-dimethylformamide: DMF; methanol: MeOH;diethyl ether: Et₂O; acetic acid: AcOH; acetonitrile: MeCN;trifluoroacetic acid: TFA; dichloromethane: DCM; dimethoxyethane: DME;diphenylphosphinoferrocene (dppf);

n-butyllithium: n-BuLi; lithium diisopropylamide: LDA

1-hydroxy-7-azabenzotriazole: HOAt

4-N,N-dimethylaminopyridine: DMAP; diisopropylethylamine: DIEA;N-methylmorpholine: NMM.

Microporous Toluene sulfonic acid resin (MP-TsOH resin)

tris-(2-aminoethyl)aminomethyl polystyrene (PS-trisamine)

methylisocyanate polystyrene (PS-NCO)

Saturated (sat.); anhydrous. (anhyd); room temperature (rt); hour (h);Minutes (Min), Retention Time (Rt); molecular weight (MW); milliliter(mL); gram (g). milligram (mg); equivalent (eq); day (d); microwave(μW); microliter (μL);

All NMR data were collected on 400 MHz NMR spectrometers unlessotherwise indicated. LC-Electrospray-Mass spectroscopy with a C-18column and 5% to 95% MeCN in water as the mobile phase was used todetermine the molecular mass and retention time. The tables contain thecompounds with retention time/observed MW and/or NMR data.

For internal consistency in the reaction schemes shown in Methods A toDF, the product of each method is shown as structure A4, B4, C3, etc.,wherein certain variables are as defined for that method, but it will beapparent that, for example, A4 has the same structure as C3. That is,different methods can be used to prepare similar compounds.

The compounds in the invention may be produced by processes known tothose skilled in the art and as shown in the following reaction schemesand in the preparations and examples described below. The tables containthe compounds with observed m/e values from mass spectroscopy and/or NMRdata. These compounds can be obtained with synthetic methods similar tothese listed in the last column using appropriate reagents.

Method A, Step 1:

To a solution of A1 (R³=CH₃ & R⁴=CH₂CH(CH₃)₂) (10 mmol, 1 eq) in 30 mlof anhyd. CH₂Cl₂ was added thiocarbonyl dipyridone (1.2 eq). Afterstirring overnight the solution was diluted with CH₂Cl₂, washed with 1NHCl, H₂O (2×), and a saturated aqueous NaCl solution (2×). The organicsolution was dried over Na₂SO₄, filtered and concentrated. The crudematerial was purified via flash chromatography to afford A2 (R³=CH₃ &R⁴=CH₂CH(CH₃)₂).

Method A, Step 2:

A solution of 3,5-difluorobenzyl amine (0.15 mmol, 1.5 eq) in THF (0.15mL) was added to a solution of A2 (R³=CH₃ & R⁴=CH₂CH(CH₃)₂) (0.1 mmol, 1eq) in anhydrous CH₂Cl₂ (1 mL). The reaction mixture was refluxedovernight. The reaction solution was added to MP-TsOH resin (2-3 eq) anddiluted with CH₃CN. The suspension was agitated overnight. The mixturewas filtered and the filtrate was concentrated to afford A3(R¹=3,5-difluorobenzyl, R³=CH₃, & R⁴=CH₂CH(CH₃)₂).

Method A, Step 3:

To a solution of A3 (R¹=3,5-difluorobenzyl, R³=CH₃, & R⁴=CH₂CH(CH₃)₂)(10 mg) in CH₃OH (1 mL) was added NH₄OH (0.44 mL) and t-butyl hydrogenperoxide (0.1 mL) and the reaction mixture was agitated for 2 d. Thesolution was concentrated, the resulting residue was dissolved in CH₃OH(1.2 mL) and was treated with sulfonic acid resin. The suspension wasagitated overnight and the resin was washed with CH₃OH (4×10 min) beforeit was treated with 2 N NH₃ in CH₃OH for 1 h. The suspension wasfiltered and the filtrate was concentrated to give the crude materialwhich was purified by preparative HPLC/LCMS eluting with a CH₃CN/H₂Ogradient to afford A4 (R¹=3,5-difluorobenzyl, R²=H, R³=CH₃, &R⁴=CH₂CH(CH₃)₂). NMR (CD₃OD): δ6.9, m, 3H, δ4.8-4.9, m; δ1.75, d, 2H,δ1.5, m, 1H, δ1.42, s, 3H, δ0.85, d, 3H, δ0.65, d, 3H. ES_LCMS (m/e)296.1.

The following compounds were synthesized using similar methods: #Structure MW Obs. m/e 1

223 224 2

223 224 3

225 226 4

225 226 5

227 228 6

237 238 7

239 240 8

239 240 9

239 240 10

240 241 11

241 242 12

241 242 13

251 252 14

253 254 15

254 255 16

255 256 17

255 256 18

255 256 19

260 261 20

260 261 21

265 266 22

265 266 23

265 266 24

267 268 25

268 269 26

268 269 27

269 270 28

273 274 29

273 274 30

274 275 31

274 275 32

274 275 33

277 278 34

279 280 35

280 281 36

280 281 37

280 281 38

280 281 39

281 282 40

282 283 41

282 283 42

282 283 43

283 284 44

285 286 45

287 288 46

287 288 47

289 290 48

293 294 49

294 295 50

294 295 51

295 296 52

296 297 53

301 302 54

303 304 55

304 305 56

304 305 57

305 306 58

307 308 59

307 308 60

308 309 61

310 311 62

317 318 63

319 320 64

322 323 65

324 325 66

327 328 67

327 328 68

327 328 69

327 328 70

328 329 71

330 331 72

331 332 73

331 332 74

335 336 75

335 336 76

337 338 77

337 338 78

342 343 79

345 346 80

345 346 81

349 350 82

349 350 83

351 352 84

351 352 85

351 352 86

359 360 87

361 362 88

361 362 89

361 362 90

363 364 91

363 364 92

363 364 93

363 364 94

363 364 95

363 364 96

369 370 97

374 375 98

375 376 99

375 376 100

377 378 101

377 378 102

377 378 103

381 382 104

382 383 105

385 386 106

385 386 107

386 387 108

389 390 109

391 392 110

391 392 111

391 392 112

391 392 113

393 394 114

393 394 115

400 401 116

401 402 117

401 402 118

401 402 119

401 402 120

403 404 121

403 404 122

403 404 123

405 406 124

405 406 125

409 410 126

409 410 127

409 410 128

409 410 129

411 412 130

413 414 131

413 414 132

414 415 133

415 416 134

415 416 135

415 416 136

417 418 137

419 420 138

421 422 139

423 424 140

425 426 141

425 426 142

425 426 143

427 428 144

429 430 145

430 431 146

430 431 147

431 432 148

433 434 149

437 438 150

439 440 151

440 441 152

440 441 153

441 442 154

441 442 155

442 443 156

447 448 157

449 450 158

455 456 159

463 464 160

463 464 161

471 472 162

473 474 163

481 482 164

481 482 165

487 488 166

488 489 167

499 500 168

504 505 169

523 524 170

525 526 171

525 526 172

527 528 173

528 529 174

535 536 175

535 536 176

535 536 177

535 536 178

550 551 179

554 555 180

556 557 181

569 570 182

581 582 183

374 NA 184

388 NA 185

337 NMR 186

351 NMR

A modified literature procedure was used (Ugi, I. Angew. Chem. 1962, 749-22).

Method B, Step 1:

To a solution of B1 (HCl salt, R¹=3-chlorophenethyl) (1.1 g, 5.73 mmol)in anhydrous CH₃OH (15 mL) was added potassium thiocyanate (0.56 g, 5.73mmol). The reaction mixture was heated to 60° C. for 1 h. The suspensionwas filtered and the filtrate was added to B5 (R³=Me, R⁴=^(i)Bu) (0.72mL, 5.73 mmol) and benzyl isocyanide (0.77 mL, 6.3 mmol). The mixturewas stirred overnight before the solution was concentrated and theresidue was purified via flash chromatography eluting with ethyl acetatein hexane to yield 0.28 g of B2 (R³=CH₃, R⁴=CH₂CH(CH₃)₂, andR¹=3-Chlorophenethyl).

Method B, Step 2:

A solution of 40% concentrated HCl in CH₃CH₂OH was added to B2 (R³=CH₃,R⁴=CH₂CH(CH₃)₂, and R¹=3-Chlorophenethyl) and the solution was heated ina microwave at 160° C. for 30 min. The solution was concentrated andpurified via reverse phase preparative HPLC eluting with a CH₃CN/H₂O(with 0.1% formic acid) gradient to afford B3 (R³=CH₃, R⁴=CH₂CH(CH₃)₂,and R¹=3-Chlorophenethyl).

Method B, Step 3:

Compound B4 (R²=H, R₃═CH₃, R⁴=CH₂CH(CH₃)₂, and R¹=3-Chlorophenethyl) wasprepared from B3 (R³=CH₃, R⁴=CH₂CH(CH₃)₂, and R¹=3-Chlorophenethyl)following a procedure similar to Method A, Step 3. NMR(CD₃OD): δ 8.1,br, 1H; δ 7.35, s, 1H; δ 7.25, m, 3H; δ 3.6, m, 1H; δ 3.4, m, 1H, δ 3.0,m, 1H, δ 2.8, m, 1H, δ 1.75, m, 1H, δ 1.6, m, 1H, δ 1.35, m, 1H, δ 1.2s, 3H; δ 0.8, m, 6H. ES_LCMS (m/e): 308.1

The following compounds were prepared using similar methods / Obs. #Structure MW m/e 545

251 252 546

293 294 547

307 308 548

357 358 549

371 372 550

413 551

265

Method C, Step 1:

A solution of C1 (R³=R⁴=CH₂CH₂CH₂CH₃) (50 mg, 0.25 mmol) and C4(R¹=3-chlorophenyl) (38 μL, 0.26 mmol) was refluxed overnight. Trisamineresin (2 eq) and polystyrene isocyanate resin (2 eq) was added and themixture was agitated. After 3 h, the suspension was filtered and theresin was washed with CH₂Cl₂ (3×) and CH₃OH (3×). The filtrate wasconcentrated to afford C2 (R¹=3-Cl—C₆H₄, R³=R⁴=CH₂CH₂CH₂CH₃) (60 mg,68%).

Method C, Step 2:

Compound C3 (R¹=3-C₁-C₆H₄, R²=H, R³=R⁴=CH₂CH₂CH₂CH₃) was prepared fromC2 (R¹=3-C₁-C₆H₄, R³=R⁴=CH₂CH₂CH₂CH₃) following a procedure similar toMethod A, Step 3. NMR(CDCl3): δ 7.4, m, 2H; δ 7.2, m, 2H; δ 5.0, s, 2H;δ 1.7, m, 4H; δ 1.1, m, 8H; δ 0.7; m, 6H. ES-LCMS (m/e): 336.1.

The following compounds were prepared using similar method. Obs. #Structure MW m/e 641

209 210 642

211 212 643

215 216 644

225 226 645

239 240 646

245 246 647

246 247 648

251 252 649

267 268 650

309 310 651

317 318 652

319 320 653

323 324 654

324 325 655

329 330 656

329 330 657

335 336 658

335 336 659

335 336 660

335 336 661

335 336 662

352 353 663

352 353 664

377 378 665

385 386 666

391 392 667

420 421 668

420 421

Method D, Step 1:

A mixture of D1 (R³=R⁴=CH₂C₆H₅) (20 g), potassium cyanide (40 g) andammonium carbonate (15 g) in ethanol (100 mL) and H₂O (200 mL) washeated in a sealed flask at 130° C. overnight to yield 25 g of D2(R³=R⁴=CH₂C₆H₅) after filtration followed by washing with water.

Method D, Step 2:

A solution of 2 N KOH (3 eq) was added to D2 (R³=R⁴=CH₂C₆H₅) (1 eq) andirradiated via microwave at 185° C. for 3 h followed by addition ofconcentrated HCl to the solution until a pH=2-3 was obtained. The solidwas filtered and washed with water to afford D3 (R³=R⁴=CH₂C₆H₅).

Method D, Step 3:

A solution of trimethylsilyldiazomethane in hexane (2 N) (2 eq) wasadded drop wise to a solution of D3 (R³=R⁴=CH₂C₆H₅) (1 eq) in anhydrousCH₃OH (30 mL). After 1 h, an additional 2 eq oftrimethylsilyldiazomethane in hexane (2 N) was added and the reactionwas stirred for 20 minutes before it was was concentrated. The residuewas dissolved in a 0.2 N HCl solution (25 mL) and washed with ether(3×). A saturated solution of Na₂CO₃ was added to the aqueous phaseuntil the pH of the solution was basic. The solution was extracted withethyl acetate (3×). The organic extracts were combined, dried overNa₂SO₄, and concentrated to afford D4 (R³=R⁴=CH₂C₆H₅).

The following amino esters were prepared using a similar method.

Method E, Step 1:

Thionyl chloride (0.47, 6.38 mmol) was added drop wise to a solution ofE1 (R³=CH₂CH₂C₆H₅) (2 g, 6.38 mmol) and benzaldehyde dimethyl acetal(0.96 mL, 6.38 mmol) in anhydrous THF at 0° C. under N₂. After 5 min,ZnCl₂ (0.87 g, 6.38 mmol) was added and the reaction mixture was stirredat 0° C. After 3 h, an additional amount of ZnCl₂ (0.18 g, 1.28 mmol)and thionyl chloride (0.1 mL, 1.28 mmol) were added and stirred for 1 hat 0° C. The reaction mixture was poured into a stirred suspension ofice/H₂O. The mixture was stirred occasionally until the ice melted. Theaqueous solution was extracted with ether (3×). The combined organicextracts were washed with H₂O (3×), a sat. aqueous solution of NaHCO₃(1×), and H₂O (2×). The organic solution was dried over Na₂SO₄, filteredand concentrated. The crude material was purified via flashchromatography eluting with ethyl acetate in hexane to yield compound E2(R³ CH₂CH₂C₆H₅).

Method E, Step 2:

A solution of lithium hexamethyldisilazide in hexane (1.0 M, 1.65 mL,1.64 mmol) was added drop wise to a solution of E2 (R³=CH₂CH₂C₆H₅) (600mg, 1.49 mmol) and HMPA (0.85 mL) in THF (6.5 mL) cooled at −78° C.under N₂. After 15 min, isobutyl iodide (0.52 mL, 4.48 mmol) was addeddrop wise and the reaction mixture was stirred at −78° C. for 3 h. Thereaction was warmed to −65° C., stirred for 2 h and warmed to rtovernight. The reaction solution was poured into a mixture of sat.NaHCO₃ (aq)/ether/ice. The aqueous layer was extracted with ether (3×).The organic extracts were combined and washed with brine (2×). Theorganic solution was dried over Na₂SO₄, filtered and concentrated. Thecrude material was purified via flash chromatography eluting with ethylacetate in hexane to yield compound E3 (R³=CH₂CH₂C₆H₅, R⁴=CH₂CH(CH₃)₂).

Method E, Step 3:

A solution of lithium methoxide (1 N in CH₃OH) (0.36 mL, 0.36 mmol) wasadded to compound E3 (R³=CH₂CH₂C₆H₅, R⁴=CH₂CH(CH₃)₂). The reactionmixture was shaken at rt for 50 min. An additional 0.55 eq of lithiummethoxide were added. After 2.5 h, a sat. aqueous solution of NaHSO₃(0.75 mL) and ethyl acetate (3 mL) was added to the reaction mixture andshaken for 15 min. The suspension was filtered. The resulting whitesolid was washed with a sat. aqueous solution of NaHSO₃ (1×) and ethylacetate (1×). The aqueous phase of the filtrate was separated andextracted with ethyl acetate (2×). The organic extracts were combinedand washed with a sat. aqueous solution of NaHSO₃ (8×). The organicsolution was dried over Na₂SO₄, filtered and concentrated to afford E4(R³=CH₂CH₂C₆H₅, R⁴=CH₂CH(CH₃)₂) (109 mg, 87%).

Method E, Step 4:

To a solution of E4 (R³=CH₂CH₂C₆H₅, R⁴=CH₂CH(CH₃)₂) (109 mg, 0.28 mmol)in CH₃OH (4 mL) was added 1 N HCl (0.28 mL, 0.28 mmol) and 20% palladiumhydroxide on carbon (22 mg). The reaction mixture was hydrogenated at 40psi. After 2.5 h, the reaction was filtered and the catalyst was washedwith CH₃OH (3×). The filtrate was concentrated to afford E5(R³=CH₂CH₂C₆H₅, R⁴=CH₂CH(CH₃)₂) (78 mg, 96%).

The following aminoesters were prepared using similar method.

A 500 mL methanol solution of 20 g of D5 (R³=benzyl, n=1) with 1.5 eq ofHCl was hydrogenated with 1 g of Rh/C (5% w/w) and 2 g of Pt/C (5% w/w)at 60 psi for 2 days. The solid was filtered and washed with excessivemethanol. The combined solution was evaporated to give 20 g of F1(R³=cyclohexylmethyl, n=1) as HCl salt.

The following amino esters were examples prepared using similar method.

Method G, Step 1:

To a solution of G1 (R¹=CH₂(3-ClC₆H₄) and R³=CH₃) (400 mg, 1.23 mmol,generated following a procedure similar to Method C, Step 1) in ethanol(5 mL) was added lithium hydroxide monohydrate (100 mg, 2.45 mmol) inH₂O (0.5 mL). After 2.5 h, another portion of lithium hydroxidemonohydrate (100 mg, 2.45 mmol) was added. After 5.5 h, the reactionmixture was diluted with H₂O (15 mL) and extracted with ether (2×). Asolution of 30% HCl was added to the aqueous phase until its pH=1 to 2.The solution was saturated with NaCl and extracted with ethyl acetate(3×). The organic solution was dried over Na₂SO₄, filtered andconcentrated to afford G2 (R¹=CH₂(3-ClC₆H₄) and R³=CH₃) (357 mg, 93%).

Method G, Step 2:

A solution of benzyl amine (1.2 eq) was added to G2 (R¹=CH₂(3-ClC₆H₄)and R³=CH₃) (1 eq), HOBT (1.5 eq) and polystyrene EDC resin (94 mg, 1.53mmol/g, 3 eq) in 1:1 THF:CH₃CN (1 mL). The reaction mixture was shakenovernight at rt. Trisamine resin (85 mg, 3.38 mmol/g, 6 eq) andisocyanate resin (100 mg, 1.47 mmol/g, 3 eq) was added. After 6 h, thesuspension was filtered and the filtrate was concentrated to afford G3(R¹=CH₂(3-ClC₆H₄), R³=CH₃, R¹⁵=CH₂C₆H₅ and R¹⁶=H).

Method G, Step 3:

Compound G4 (R¹=CH₂(3-ClC₆H₄), R²=H, R³=CH₃, R¹⁵=CH₂C₆H₅ and R¹⁵=H) wasprepared from G3 (R¹=CH₂(3-ClC₆H₄), R³=CH₃, R¹⁵=CH₂C₆H₅ and R¹⁶=H)following a procedure similar to Method A, Step 3.

The following compounds were prepared using similar methods. Obs. #Structure MW m/e 669

322 323 670

334 335 671

336 337 672

348 349 673

364 365 674

364 365 675

376 377 676

384 385 677

390 391 678

393 394 679

398 399 680

398 399 681

406 407 682

412 413 683

414 415 684

414 415 685

414 415 686

421 422 687

428 429 688

434 435 689

442 443 690

449 450 691

461 462 692

511 512 693

511 512

Method H, Step 1:

To a solution of H1 (R³=CH₃) (5 g, 39 mmol) in a 1:1 mixture of 0.5 MNaHCO₃:CH₃CH₂OH was added R¹-NCS (R¹=3-chlorobenzyl) (11.5 mL, 78 mmol).The reaction mixture was heated at 50° C. overnight. The reaction wascooled and diluted with water. The aqueous phase was extracted withethyl acetate (5×). The organic extracts were combined, washed withwater (2×) and dried over Na₂SO₄. The solution was filtered and solventwas removed to give a small volume of solution. Hexane was added and theresulting suspension was filtered to yield 6.8 g of a solid H2 (R³=CH₃,R¹=CH₂(3-ClC₆H₄)) (61%).

Method H, Step 2:

Compound H3 (R³=CH₃, R¹=CH₂(3-ClC₆H₄)) was synthesized from H2 (R³=CH₃,R¹=CH₂(3-ClC₆H₄)) following a procedure similar to Method A, Step 3.

Method H, Step 3:

To a solution of crude H3 (R³=CH₃, R¹=CH₂(3-ClC₆H₄)) (14 mmol) in a 1:3mixture of CH₃OH:THF was added 0.5 M NaHCO₃ in H₂O (28 mL, 14 mmol) anddi-tert-butyl dicarbonate (3.69 g, 16.9 mmol). The reaction was stirredat rt for 2.5 h and then stored at −10° C. overnight. The reaction wasdiluted with brine and extracted with ethyl acetate (4×). The organicextracts were combined and washed with brine (1×). The organic solutionwas dried over Na₂SO₄, filtered and concentrated. The crude material waspurified via flash chromatography eluting with ethyl acetate in hexaneto afford 1.5 g of H4 (R¹=CH₂(3-ClC₆H₄) and R³=CH₃).

Method H, Step 4:

A solution of triflic anhydride (128 μL, 0.76 mmol) in CH₂Cl₂ (5 mL) wasadded drop wise to a solution of H4 (R¹=CH₂(3-ClC₆H₄) and R³=CH₃) (200mg, 0.55 mmol) and 2,6-lutidine (176 μL, 2.18 mmol) at −30° C. Thereaction mixture was stirred for 1.5 h. Water (10 mL) was added at −20°C. and the ice bath was removed. The reaction was stirred until itreached 0° C. The organic layer was separated, dried over Na₂SO₄,filtered and concentrated to afford 310 mg of H5 (R¹=CH₂(3-ClC₆H₄) andR³=CH₃).

Method H, Step 5:

A solution of crude H5 (R¹=CH₂(3-ClC₆H₄) and R³=CH₃) (0.11 mmol) and 7Nammonia in Methanol (R²¹—H═NH₂—H) (10 eq) was stirred overnight at rt.The reaction solution was concentrated. The crude material was purifiedusing reverse phase preparative HPLC eluting with a CH₃CN/H₂O gradientwith 0.1% formic acid to yield H6 (R¹=CH₂(3-ClC₆H₄), R³=CH₃, R²¹=NH₂).

Method H, Step 6:

A solution of 50% trifluoroacetic acid in CH₂Cl₂ (2 mL) was added to H6(R¹=CH₂(3-ClC₆H₄), R³=CH₃, R²¹=NH₂). After 40 min the solvent wasevaporated and residue purified by preparative HPLC/LCMS eluting with aCH₃CN/H₂O gradient to afford H7 (R¹=CH₂(3-ClC₆H₄), R₃═CH₃, R²¹=NH₂). NMR(CDCl₃), δ 7.45, m, 3H; δ 7.35, m, 1H; δ 4.9, m, 2H; δ 3.5, m, 2H; δ1.65, s, 3H. ES_LCMS (m/e) 267.07.

The following compounds were prepared using similar methods. Obs. #Structure MW m/e 694

238 239 695

248 249 696

257 258 697

264 265 698

266 267 699

292 293 700

308 309 701

314 315 702

320 321 703

328 329 704

334 335 705

342 343 706

354 355 707

372 373 708

418 419 709

483 484

Method I, Step 1:

Diethylaminomethyl polystyrene resin (5 eq) was added to a solution ofthe formate salt of I1 (R¹=CH₂(3-ClC₆H₄), R³=CH₃ and R¹⁶=H) in CH₂Cl₂and the suspension was agitated. After 15 min, the mixture was filteredand the resin was washed with CH₂Cl₂ (4×). The filtrate was concentratedto afford the free base I1 (R¹=CH₂(3-ClC₆H₄), R³=CH₃ and R⁶═H).

A solution of R¹⁵COOH(R⁵=Phenethyl) (1.3 eq) was added to a mixture ofEDC resin (41 mg, 1.53 mmol/g, 3 eq), HOBT (1.5 eq), and the free baseof I1 (R¹=CH₂(3-ClC₆H₄), R³=CH₃ and R⁶═H) (0.021 mmol) in 1:1 CH₃CN:THF.The suspension was agitated overnight. Polystyrene isocyanate resin (45mg, 3 eq), polystyrene trisamine resin (40 mg, 6 eq) and a 1:1 mixtureof CH₃CN:THF (0.5 mL) was added. The mixture was agitated for 6 h. Thesuspension was filtered and the filtrate was concentrated to afford 12(R¹=CH₂(3-ClC₆H₄), R³=CH₃, R¹⁶=H and R¹⁵=CH₂CH₂C₆H₅).

Method I, Step 2:

I3 (R¹=CH₂(3-ClC₆H₄), R³=CH₃, R¹⁶=H and R¹⁵=CH₂CH₂C₆H₅) was preparedfrom I2 (R¹=CH₂(3-ClC₆H₄), R³=CH₃, R¹⁶=H and R¹⁵=CH₂CH₂C₆H₅) usingmethod similar to method H step 6.

The following compounds were prepared using similar method. Obs. #Structure MW m/e 710

280 281 711

308 309 712

308 309 713

334 335 714

342 343 715

362 363 716

372 373 717

376 377 718

398 399 719

406 407 720

410 11 721

410 11 722

414 15 723

420 21 724

428 29 725

511 12

Method J, Step 1:

Diethylaminomethyl polystyrene resin (5 eq) was added to a solution ofJ1 (TFA salt, R¹=CH₂(3-ClC₆H₄) and R³=CH₃) in CH₂Cl₂ and the suspensionwas agitated. After 15 min, the mixture was filtered and the resin waswashed with CH₂Cl₂ (4×). The filtrate was concentrated to afford thefree base. A solution of R¹⁵NCO (R¹⁵=butyl) (2 eq) in CH₂Cl₂ was addedto the free base of J1 (R¹=CH₂(3-ClC₆H₄) and R³=CH₃) (0.021 mmol) in 1:1CH₃CN:THF. The suspension was agitated overnight. Polystyrene isocyanateresin (45 mg, 3 eq), polystyrene trisamine resin (40 mg, 6 eq) and a 1:1mixture of CH₃CN:THF (0.5 mL) was added. The mixture was agitated for 6h. The suspension was filtered and the filtrate was concentrated toafford J2 (R¹=CH₂(3-ClC₆H₄), R³=CH₃, and R¹⁵=CH₂CH₂CH₂CH₃).

Method J, Step 2:

Compound J3 (R¹=CH₂(3-ClC₆H₄), R³=CH₃, and R¹⁵=CH₂CH₂CH₂CH₃) wasprepared from J2 (R¹=CH₂(3-ClC₆H₄), R³=CH₃, and R¹⁵=CH₂CH₂CH₂CH₃)following the procedure described in Method H, Step 2.

The following compounds were prepared using similar method. Obs. #Structure MW m/e 726

323 324 727

337 338 728

352 729

358 730

365 366 731

377 378 732

413 414 733

417 418 734

421 422 735

425 426

Method K, Step 1:

A solution of R¹⁵SO₂Cl (R¹⁵=Propyl)(1.5 eq) was added to a suspension ofpolystyrene diisopropylethylamine resin (18 mg, 3.45 mmol/g, 3 eq) andthe free base of K1 prepared using method H (R¹=CH₂(3-ClC₆H₄) andR³=CH₃) (0.021 mmol) in 1:1 CH₃CN:THF. The suspension was agitatedovernight. Polystyrene isocyanate resin (45 mg, 3 eq), polystyrenetrisamine resin (40 mg, 6 eq) and a 1:1 mixture of CH₃CN:THF (0.5 mL)was added. The mixture was agitated for 6 h. The suspension was filteredand the filtrate was concentrated to afford K2 (R¹=CH₂(3-ClC₆H₄),R³=CH₃, and R¹⁵=CH₂CH₂CH₃).

Method K, Step 2:

Compound K3 (R¹=CH₂(3-ClC₆H₄), R³=CH₃, and R¹⁵=CH₂CH₂CH₃) was preparedfrom K2 (R¹=CH₂(3-ClC₆H₄), R³=CH₃, and R¹⁵=CH₂CH₂CH₃) following theprocedure described in Method H, Step 6.

The following compounds were prepared using similar method. Obs. #Structure MW m/e 736

316 317 737

344 345 738

372 373 739

378 379 740

442 443 741

454 455 742

492 493

(In the scheme, -Z-NH—C(O)R¹⁶—is equivalent to R⁵¹ substituted by R²¹,or R¹ Subsitituted by alkyl-R²², wherein R²¹ and R²² are —N(R¹⁵)C(O)R¹⁶and R¹⁵ is H, and wherein Z is optionally substituted alkylene-arylene,alkylene-arylene-alkylene, alkylene-heteroarylene,alkylene-heteroarylene-alkylene, alkylene-cycloalkylene,alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene,alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene,cycloalkylene or heterocycloalkylene)

Method L, Step 1:

A solution of L1 (R³=CH₃ and R⁴=CH₂CH(CH₃)₂) (1 eq) andZ=-paramethylene-benzyl) (1.05 eq) in CH₂Cl₂ was stirred at rt. Thereaction solution was concentrated and purified via flashchromatography. The material was treated with 50% trifluoroacetic acidin CH₂Cl₂ for 30 min. The solution was concentrated. The residue wasdissolved in 1 N HCl (10 mL) and washed with ether (2×). A saturatedsolution of Na₂CO₃ in H₂O was added to the aqueous phase until thesolution became basic. The solution was extracted with CH₂Cl₂ (3×). TheCH₂Cl₂ extracts were combined, dried over Na₂SO₄, filtered andconcentrated to yield L2 (R³=CH₃, R⁴=CH₂CH(CH₃)₂,Z=para-(CH₂)C₆H₄(CH₂)—).

Method L, Step 2:

Compound L3 (R³=CH₃, R⁴=CH₂CH(CH₃)₂, Z=para-(CH₂)C₆H₄(CH₂)—,R¹⁶=CH₂CH₂CH₂CH₃) was prepared from L2 (R³=CH₃, R⁴=CH₂CH(CH₃)₂,Z=para-(CH₂)C₆H₄(CH₂)—) following the procedure described in Method I,Step 1.

Method L, Step 3:

Compound L4 (R³=CH₃, R⁴=CH₂CH(CH₃)₂, Z=para-(CH₂)C₆H₄(CH₂)—,R¹=CH₂CH₂CH₂CH₃) was prepared from (R³=CH₃, R⁴=CH₂CH(CH₃)₂,Z=para-(CH₂)C₆H₄(CH₂)—, R¹⁶=CH₂CH₂CH₂CH₃) following the proceduredescribed in Method A, Step 3.

The following compounds were prepared using similar method. Obs. #Structure MW m/e 743

316 317 744

316 317 745

330 331 746

330 331 747

344 345 748

344 345 749

358 359 750

358 359 751

386 387 752

386 387 753

386 387 754

400 401 755

400 401 756

420 421 757

434 435 758

434 435 759

436 437 760

436 437 761

450 451 762

450 451 763

450 451 764

450 451 765

464 465 766

464 465 767

470 471 768

478 479 769

478 479 770

484 485 771

484 485 772

492 493 773

492 493 774

519 520 775

519 520 776

533 534 777

533 534

(In the scheme, -Z-NH—C(O)—NHR¹⁵— is equivalent to R¹ substituted byR²¹, or R¹ Subsitituted by alkyl-R²², wherein R²¹ and R²² are—N(R¹⁶)—C(O)—NHR¹⁵ and R¹⁶ is H, and wherein Z is optionally substitutedalkylene-arylene, alkylene-arylene-alkylene, alkylene-heteroarylene,alkylene-heteroarylene-alkylene, alkylene-cycloalkylene,alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene,alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene,cycloalkylene or heterocycloalkylene)

Method M, Step 1:

Compound M2 (R³=CH₃, R⁴=CH₂CH(CH₃)₂, Z=para-(CH₂)C₆H₄(CH₂)—,R¹⁵=3,4-difluorophenyl) was prepared from M1 (R³=CH₃, R⁴=CH₂CH(CH₃)₂,Z=para-(CH₂)C₆H₄(CH₂)—) following the procedure described in Method J,Step 1.

Method M, Step 2:

Compound M3 (R³=CH₃, R⁴=CH₂CH(CH₃)₂, Z=para-(CH₂)C₆H₄(CH₂)—,R¹⁵=3,4-difluorophenyl) was prepared from M2 (R³=CH₃, R⁴=CH₂CH(CH₃)₂,Z=para-(CH₂)C₆H₄(CH₂)—, R¹⁵=3,4-difluorophenyl) following the proceduredescribed in Method A, Step 3. NMR(CD₃OD) δ 7.45, m, 1H; δ 7.26, m, 4H;7.24, m, 1H, δ 6.96, m, 1H, δ 4.8, m; δ 4.3, s, 2H; δ 1.69, m, 2H, δ1.44, m, 1H; δ 1,37, s, 3H; δ 0.8, m, 3H; δ 0.63, m, 3H. ES_LCMS (m/e)430.27

The following compounds were prepared using similar method. Obs. #Structure MW m/e 778

331 332 779

359 360 780

359 360 781

373 374 782

373 374 783

373 374 784

373 374 785

387 388 786

387 388 787

387 388 788

387 388 789

401 402 790

401 402 791

405 406 792

407 408 793

407 408 794

407 408 795

413 414 796

413 414 797

418 419 798

418 419 799

421 422 800

421 422 801

421 422 802

421 422 803

421 422 804

421 422 805

421 422 806

421 422 807

423 424 808

423 424 809

423 424 810

423 424 811

425 426 812

425 426 813

427 428 814

429 430 815

429 430 816

429 430 817

432 433 818

432 433 819

432 433 820

433 434 821

433 434 822

435 436 823

435 436 824

435 436 825

435 436 826

435 436 827

435 436 828

435 436 829

437 438 830

437 438 831

437 438 832

437 438 833

437 438 834

437 438 835

437 438 836

439 440 837

439 440 838

439 440 839

441 442 840

441 442 841

441 442 0842

441 442 843

443 444 844

443 444 845

443 444 846

447 448 847

447 448 848

449 450 849

450 451 850

450 451 851

450 451 852

451 452 853

451 452 854

451 452 855

452 453 856

453 454 857

453 454 858

455 456 859

455 456 860

455 456 861

457 458 862

457 458 863

457 458 864

458 459 865

458 459 866

460 461 867

461 462 868

461 462 869

461 462 870

461 462 871

461 462 872

461 462 873

461 462 874

463 464 875

466 467 876

466 467 877

467 468 878

469 470 879

469 470 880

471 472 881

471 472 882

472 473 883

472 473 884

475 476 885

475 476 886

475 476 887

475 476 888

475 476 889

475 476 890

475 476 891

475 476 892

475 476 893

475 476 894

475 476 895

475 476 896

477 478 897

477 478 898

479 480 899

479 480 900

480 481 901

483 484 902

483 484 903

485 486 904

485 486 905

485 486 906

485 486 907

485 486 908

489 490 909

489 490 910

489 490 911

491 492 912

493 494 913

493 494 914

493 494 915

493 494 916

496 497 917

496 497 918

497 498 919

497 498 920

499 500 921

501 502 922

501 502 923

502 503 924

502 504 925

502 503 926

502 503 927

503 504 928

505 506 929

507 508 930

507 508 931

507 508 932

509 510 933

509 510 934

509 510 935

510 511 936

511 512 937

511 512 938

514 515 939

515 516 940

515 516 941

519 520 942

519 520 943

522 523 944

523 524 945

545 524 946

525 526 947

527 528 948

529 530 949

533 534 950

537 538 951

539 540 952

543 544 953

545 546 954

545 546 955

547 548 956

549 550 957

553 554 958

555 556 959

559 560 960

559 560 961

387

(In the scheme, -Z-NH—S(O)₂R¹⁶—is equivalent to R¹ substituted by R²¹,or R¹ Subsitituted by alkyl-R²², wherein R²¹ and R²² are—N(R¹⁶)—C(O)—NHR¹⁵ and R¹⁶ is H, and wherein Z is optionally substitutedalkylene-arylene, alkylene-arylene-alkylene, alkylene-heteroarylene,alkylene-heteroarylene-alkylene, alkylene-cycloalkylene,alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene,alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene,cycloalkylene or heterocycloalkylene)

Method N, Step 1:

Compound N2 (R³=CH₃, R⁴=CH₂CH(CH₃)₂, Z=para-(CH₂)C₆H₄(CH₂)—,R¹⁶=CH₂CH(CH₃)₂) was prepared from N1 (R³=CH₃, R⁴=CH₂CH(CH₃)₂,Z=para-(CH₂)C₆H₄(CH₂)—) following the procedure described in Method K,Step 1.

Method N, Step 2:

Compound N3 (R³=CH₃, R⁴=CH₂CH(CH₃)₂, Z=para-(CH₂)C₆H₄(CH₂)—,R¹⁶=CH₂CH(CH₃)₂) was prepared from N2 (R³=CH₃, R⁴=CH₂CH(CH₃)₂,Z=para-(CH₂)C₆H₄(CH₂)—, R¹⁶=CH₂CH(CH₃)₂) following the proceduredescribed in Method A, Step 3.

The following compounds were prepared using similar method. Obs. #Structure MW m/e 962

380 381 963

380 381 964

394 395 965

394 395 966

451 452 967

484 485 968

484 485 969

498 499 970

498 499

Method O, Step 1:

A solution of indole-6-methanol (400 mg, 2.72 mmol),tert-butyldimethysilyl choride (816 mg, 5.41 mmol) and imidazole (740mg, 10.9 mmol) in CH₂Cl₂ was stirred at rt. overnight before the solventwas evaporated and residue chromatographed using ethylacetate/hexane togive product O2.

Method O, Step 2:

To a solution of O2 (200 mg, 0.77 mmol) in THF (10 mL) at −78° C. wasadded butyl lithium (1.2 eq). The solution was stirred at −78° C. for 5min and then warmed to rt. The reaction mixture was cooled to −78° C.and p-toluenesulfonyl chloride was added. The solution was warmed to rtand stirred overnight. The reaction was quenched with a saturatedaqueous K₂CO₃ solution, extracted with ethyl acetate and CH₂Cl₂. Thecrude material was purified via flash chromatography usingethylacetate/hexane to afford 360 mg of O3.

Method O, Step 3:

A solution butyl lithium (1.2 eq) was added to a solution of O3 (340 mg,0.829 mmol) in THF (20 mL). The reaction mixture was stirred for 15 minat −78° C. then sulfur dioxide was bubbled through the solution for 15min. Hexane (100 mL) was added to the reaction mixture. The reactionmixture was evaporated to afford O4 which was used in the next stepwithout further purification.

Method O, Step 4:

To a solution of O4 (0.829 mmol) in CH₂Cl₂ cooled to 0° C. was addedN-chlorosuccinimide (220 mg, 1.66 mmol). After 2 h of stirring, thesolution was filtered through a Celite plug. The filtrate wasconcentrated to afford O5.

Method O, Step 5:

To a solution of O5 in anhydrous pyridine (3 mL) was added butyl amine(100 μL). The reaction was agitated at rt for 4 d. The reaction mixturewas partitioned between 1 N HCl and CH₂Cl₂. The organic layer wasseparated and washed with 1 N HCl (3×). The organic solution was driedover Na₂SO₄, filtered and concentrated. The crude material was purifiedvia flash chromatography using ethylacetate/hexane to yield 06.

Method O, Step 6:

To a solution of O6 (70 mg) in THF was added TBAF. The reaction wasstirred at rt. before the reaction mixture was chromatographed usingethylacetate/hexane to afforded 50 mg of O7 (95%).

Method O, Step 7:

To a solution of O7 (50 mg) in CH₂Cl₂ (5 mL) was added thionyl chloride(1 mL) the reaction was stirred for 5 min and then evaporated to affordO8.

Method O, Step 8:

To a solution of O8 in CH₃OH (5 mL) was added sodium azide (50 mg). Thesolution was stirred at rt overnight and solvent evaporated. The residuewas chromatographed using ethylacetate/hexane to afforded O9 afterpurification.

Method O, Step 9:

To a suspension of O9 (70 mg) in CH₃OH was added 1 eq HCl (aq) andpalladium on carbon. The reaction mixture was hydrogenated at 1 atm for20 min to yield 90 mg of crude product O10.

Method O, Step 10:

A solution of lithium hydroxide (30 mg) in H₂O was added to a solutionof O10 (40 mg) in CH₃OH (3 mL). The reaction was stirred at rt for 2 hand an additional portion of LiOH (40 mg) was added and solution wasstirred for 2 more hours. The solvent was evaporated and residuechromatographed using ethylacetate/hexane to afforded O11.

Method P, Step 1:

A 300 mL of THF solution of 100 g of P1 (R²³=n-Pr) was added to asuspension of 38 g of LAH in 2 L of anhydrous THF at 0 C. The reactionmixture is stirred at r.t. for 1 h before 30 ml of H₂O, 90 ml of 15%NaOH was added at 0° C. The mixture was stirred at r.t. for one hourbefore Na₂SO₄ (anh) was added, the mixture was filtered, and thesolution evaporated to give a product which was dried under vacuoovernight. This product was dissolved in 600 ml of DCM and the solutionwas added into a solution of oxalyl chloride (37.3 ml) and DMSO (60.8ml) in 1.4 L of DCM at −78° C. over 40 min before Diisopropylethylamine(299 ml) was added at −78° C. The reaction was allowed to reach −10° C.The reaction was quenched with 1 L H₂O at −10° C. and the mixture wasextracted with DCM. After removal of solvent, P2 (R²³=Pr, 106 g) wasobtained. The crude material was used for next step withoutpurification.

Method P, Step 2:

To a 1.5 L DCM solution of P2 (R²³=Pr, 106 g) was addedp-Boc-aminomethylbenzylamine (1.1 eq) and sodium triacetoxyborohydride(1.1 eq) and the reaction was stirred at r.t. overnight. The reactionwas quenched with H₂O and content extracted with DCM. After removal ofsolvents the residue was chromatographed using a silica gel columneluted with 3% MeOH in DCM to give 42.5 g of P3 (R²³=Pr).

Method P, Step 3:

A 10 ml MeOH solution of P3 (R²³=Pr, 110 mg) was hydrogenated using Pd/C(5%, 11 mg) at 1 atm of hydrogen to give product P4 (R²³=Pr) afterremoval of solvent and catalyst.

Method P, Step 4:

To a 10 ml DCM solution of P4 at 0° C. (R₂₃=Pr) was added triphosgene1.2 eq) and triethylamine (2.4 eq) and the solution was stirred at 0 Cfor 2 h before the reaction was extracted with DCM/H₂O. After removal ofthe solvent, the residue was chromatographed using a silica gel columneluted with EtOAc/Hexane to give a white solid which was treated with 2NHCl in dioxane for 2 h. After removal of the solvent, compound P5(R²³=Pr) as a white solid was obtained (80 mg).The following compounds were synthesized using similar methods:

Method Q, Step 1

At room temperature, Q1 (R³=Me; R⁴=iBu) (1.00 g) and 08 (n=1, p=2, m=1)(1.24 g) in dichloromethane (30 mL) were stirred for 42 h. This mixturewas concentrated in vacuo to give an amber oil which was purified on acolumn of silica gel (200 mL) eluted with ethylacetate/hexane to give Q2(n=1, p=2, m=1, R³=Me; R⁴=iBu), a colorless oil (1.59 g).

Method Q, Step 2

Compound Q3 (n=1, p=2, m=1, R²=H, R³=Me; R⁴=iBu) was prepared from Q2(n=1, p=2, m=1, R³=Me; R⁴=iBu) using method similar to method A step 3.

Method Q, Step 3

Compound Q3 (n=1, p=2, m=1, R²=H, R³=Me; R⁴=iBu) (1.37 g) in anhydrousdichloromethane (25 mL) was treated with di-tert-butyl dicarbonate (0.68g, 1.1 equiv.) and diisopropylethylamine (0.66 mL, 1.1.equiv.). Theresulting solution was stirred at room temperature for 20 h before itwas diluted with dichloromethane and washed with 1N hydrochloric acid.The dried dichloromethane solution was concentrated in vacuo to give acolorless film (1.32 g) which was purified on a column of silica gel(125 mL) and eluted with hexane:ethyl acetate to give compound Q4 (n=1,p=2, m=1, R²=H, R³=Me; R⁴=i-Bu) as a white foam (0.74 g).

Method Q, Step 4

Compound Q4 (n=1, p=2, m=1, R²=H, R³=Me; R⁴=^(i)Bu) (0.540 g) inabsolute EtOH (20 mL) was hydrogenated with 10% Pd/C (0.400 g) at 1 atmfor 2 h. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give Q5 (n=1, p=2, m=1, R²=H, R³=Me; R⁴=^(i)Bu)as a colorless oil (0.35 g).

Method Q, Step 5

Compound Q5 (n=1, p=2, m=1, R²=H, R³=Me; R⁴=iBu) (0.012 g) and HOBt(0.005 g) dissolved in acetonitrile (0.8 mL) and tetrahydrofuran (0.25mL) was treated with EDC resin (0.080 g, 3 eq., 1.53 mmol/g) in amicrotiter plate well followed by addition of a 1M dichloroethanesolution of R¹⁵—COOH (40 uL, 1.25 eq.). After the well was capped andshaken for 18 h, the mixture was filtered and the resin washed withacetonitrile (0.5 mL). The combined solution was treated with Trisamineresin (0.050 g, 6 eq., 4.23 mmol/g) and Isocyanate resin (0.067 g, 3eq., 1.53 mmol/g) for 18 h before the solution was filtered and thesolvent was removed in vacuo to give Q6 (n=1, p=2, m=1, R²=H, R³=Me;R⁴=Bu, R¹⁵=Me).

Method Q, Step 6.

A dichloromethane solution (1.0 mL) of Q6 (n=1, p=2, m=1, R²=H, R³=Me;R⁴=^(i)Bu, R¹⁶=Me) was mixed with trifluoroacetic acid (1.0 mL) and thesolution was shaken for 2 h before it was concentrated. Diethyl ether(0.5 mL) was added and then concentrated in vacuo to give a residue,which was was purified on a Prep LCMS unit to give Q7 (=1, p=2, m=1,R²=H, R₃=Me; R₄=iBu, R₁₅=Me). NMR (CDCl₃): δ 8.38, br, 2H; δ 4.56, m,1H; δ 3.79, m, 1H; δ 3.57, m, 2H, δ 2.99, m, 1H, δ 2.48, m, 1H, δ 2.04,s, 3H, δ 1.95, m, 1H, δ 1.5-1.8, m, 5H; δ 1.5, s, 3H, 1.25, m, 2H; δ0.95, m, 3H; δ 0.85, m, 3H. ES_LCMS (m/e) 309.17.

The following compounds were prepared using similar methods: Obs. #Structure MW m/e  971

308 309  972

308 309  973

310 311  974

322 323  975

324 325  976

334 335  977

336 337  978

348 349  979

348 349  980

0 351  981

350 351  982

350 351  983

360 361  984

360 361  985

362 363  986

362 363  987

364 365  988

364 365  989

364 365  990

370 371  991

370 371  992

376 377  993

376 377  994

376 377  995

378 379  996

378 379  997

378 379  998

378 379  999

379 380 1000

384 385 1001

384 385 1002

384 385 1003

386 387 1004

388 389 1005

389 390 1006

390 391 1007

390 391 1008

390 391 1009

390 391 1010

390 391 1011

390 391 1012

390 391 1013

390 391 1014

390 391 1015

392 393 1016

392 393 1017

392 393 1018

394 395 1019

398 399 1020

398 399 1021

398 399 1022

398 399 1023

398 399 1024

400 401 1025

400 401 1025

400 401 1026

400 401 1027

400 401 1028

400 401 1029

400 401 1030

400 401 1031

400 401 1032

402 403 1033

402 403 1034

404 405 1035

404 404 1036

404 405 1037

404 405 1038

404 405 1039

404 405 1040

404 405 1041

404 405 1042

409 410 1043

410 411 1044

0 411 1045

410 411 1046

412 413 1047

412 413 1048

412 413 1049

414 415 1050

414 415 1051

414 415 1052

414 415 1053

414 415 1054

414 415 1055

414 415 1056

416 417 1057

416 417 1058

417 418 1059

418 419 1060

418 419 1061

418 419 1062

418 419 1063

418 419 1064

420 421 1065

423 424 1066

424 415 1067

424 425 1068

426 427 1069

426 427 1070

426 427 1071

426 427 1072

426 427 1073

427 428 1074

428 429 1075

428 429 1076

428 429 1077

428 429 1078

428 429 1079

430 431 1080

430 431 1081

430 431 1082

432 433 1083

432 433 1084

432 433 1085

432 433 1086

432 433 1087

432 433 1088

438 439 1089

438 439 1090

438 439 1091

438 439 1092

438 439 1093

440 441 1094

440 441 1095

440 441 1096

440 441 1097

442 443 1098

442 443 1099

442 443 1100

442 443 1101

442 443 1102

444 445 1103

444 445 1104

444 445 1105

446 447 1106

446 447 1107

446 447 1108

449 450 1109

451 452 1110

452 453 1111

452 453 1112

452 453 1113

456 457 1114

456 457 1115

456 457 1116

458 459 1117

460 461 1118

460 461 1119

460 461 1120

460 461 1121

462 463 1122

462 463 1123

462 463 1124

462 463 1125

462 463 1126

464 465 1127

466 467 1128

466 467 1129

470 471 1130

472 473 1131

474 475 1132

474 475 1133

476 477 1134

476 477 1135

478 479 1136

482 483 1137

482 483 1138

482 483 1139

488 489 1140

490 491 1141

500 501 1142

502 503 1143

502 503 1144

504 505 1145

504 505 1146

504 505 1147

511 512 1148

512 513 1149

512 513 1150

520 521 1151

520 521 1152

520 521 1153

520 521 1154

522 523 1155

522 523 1156

536 537 1157

536 537 1158

536 537 1159

538 539 1160

538 539 1161

540 541 1162

541 542 1163

542 543 1164

546 547 1165

546 547 1166

550 551 1167

550 551 1168

569 570 1169

582 583 1170

582 583 1171

584 585 1172

584 585 1173

594 595 1174

596 597 1175

596 597

Method R, Step 1.

A solution of R¹ (n=1, p=2, m=1, R²=H, R³=Me; R⁴=^(i)Bu) (0.010 g) inacetonitrile (0.85 mL) and dichloroethane (0.15 mL) was put into amicrotiter plate well followed by addition of 0.12 ml of 0.5Mphenylisocyanate solution in dichloroethane. The well was sealed and theplate shaken for 20 h before the mixture was filtered and the solidwashed with acetonitrile (0.5 ml). The combined solution was treatedwith Trisamine resin (0.050 g, 6 eq., 4.23 mmol/g) and Isocyanate resin(0.067 g, 3 eq., 1.53 mmol/g) and the mixture was shaken for 18 h. Themixture was filtered and the solution was evaporated to give R² (n=1,p=2, m=1, R²=H, R³=Me; R⁴=^(i)Bu and R¹⁵=Ph).

Method R, Step 2.

Procedure similar to Method Q, step 6 was used for the transformation ofR² (n=1, p=2, m=1, R²=H, R³=Me; R⁴=^(i)Bu and R¹⁵=Ph) to R³ (n=1, p=2,m=1, R²=H, R³=Me; R⁴=^(i)Bu and R⁵=Ph).

The following compounds were prepared using similar methods: Obs. #Structure MW m/e 1176

309 310 1177

309 310 1178

311 312 1179

325 326 1180

337 338 1181

346 347 1182

351 352 1183

351 352 1184

351 352 1185

365 366 1186

365 366 1187

365 366 1188

367 368 1189

377 378 1190

381 382 1191

385 386 1192

391 392 1193

393 394 1194

395 396 1195

399 400 1196

399 400 1197

399 400 1198

399 400 1199

399 400 1200

401 402 1201

403 404 1202

403 404 1203

407 408 1204

407 408 1205

410 411 1206

410 411 1207

413 414 1208

413 414 1209

415 416 1210

415 416 1211

415 416 1212

415 416 1213

417 418 1214

419 420 1215

419 420 1216

419 420 1217

421 422 1218

421 422 1219

425 426 1220

427 428 1221

427 428 1222

429 430 1223

429 430 1224

431 432 1225

431 432 1226

433 434 1227

435 436 1228

441 442 1229

441 442 1230

441 442 1231

445 446 1232

449 450 1233

453 454 1234

453 454 1235

453 454 1236

453 454 1237

453 454 1238

455 456 1239

455 456 1240

457 458 1241

461 462 1242

463 464 1243

467 468 1244

467 468 1245

471 472 1246

475 476 1247

477 478 1248

477 478 1249

487 488 1250

487 488 1251

487 488 1252

491 492

Method S, Step 1.

A solution of S1 (n=1, p=2, m=1, R²=H, R³=Me; R⁴=iBu) (0.010 g) inacetonitrile (0.85 mL) and dichloroethane (0.15 mL) was put into amicrotiter plate followed by addition of DIPEA-MP resin (0.030 g, 4 eq)and phenylsulfonyl chloride in dioxane (1M, 45 μL, 0.045 mmol. The wellwas capped and shaken for 18 h before it was filtered and residue washedwith acetonitrile (0.5 mL). The combined solution was treated withTrisamine resin (0.040 g, 6 eq., 4.23 mmol/g) and Isocyanate resin(0.060 g, 3 equiv., 1.53 mmol/g) and shaken for 18 h before the mixturewas filtered and the solvent removed to give S2 (n=1, p=2, m=1, R²=H,R³=Me; R⁴=iBu and R¹⁵=Ph).

Method S, Step 2.

Procedure similar to Method Q, step 6 was used for the transformation ofS2 to S3 (n=1, p=2, m=1, R²=H, R³=Me; R⁴=Bu and R¹⁵=Ph).

The following compounds were prepared using similar methods: Obs. #Structure MW m/e 1253

344 345 1254

344 345 1255

358 359 1256

358 359 1257

360 361 1258

372 373 1259

372 373 1260

386 387 1261

406 407 1262

406 407 1263

406 407 1264

412 413 1265

416 417 1266

420 421 1267

420 421 1268

420 421 1269

420 421 1270

420 421 1271

420 421 1272

424 425 1273

424 425 1274

424 425 1275

431 432 1276

432 433 1277

434 435 1278

434 435 1279

436 437 1280

436 437 1281

438 439 1282

440 441 1283

440 441 1284

440 441 1285

442 443 1286

442 443 1287

442 443 1288

442 443 1289

442 443 1290

446 447 1291

448 449 1292

448 449 1293

448 449 1294

454 455 1295

456 457 1296

456 457 1297

458 459 1298

458 459 1299

458 459 1300

462 463 1301

464 465 1302

466 467 1303

466 467 1304

466 467 1305

466 467 1306

470 471 1307

474 475 1308

474 475 1309

474 475 1310

474 475 1311

474 475 1312

474 475 1313

474 475 1314

474 475 1315

474 475 1316

474 475 1317

476 477 1318

480 481 1319

482 483 1320

484 485 1321

484 485 1322

488 489 1323

490 491 1324

490 491 1325

492 493 1326

498 499 1327

508 509 1328

508 509 1329

508 509 1330

508 509 1331

542 543 1332

557 558

Method T, Step 1.

To a microtiter plate well containing 1 ml solution of T1 (n=1, p=2,m=1, R²=H, R³=Me; R⁴=iBu) in DCM (0.010 g) and R¹⁵C(O)R¹⁶ (5 equiv,R¹⁵=H, R¹⁶=Ph) was added Sodium cyanoborohydride in dichloroethane (14.3mg/mL, 2 equiv.). The well was capped and shaken for 20 h before MP-TsOHResin (100 mg, 1.29 mmol/g) was added to the well followed by additionalMP-TsOH resin (50 mg) after 2 h. After the mixture was shaken foranother 1 h, the mixture was filtered and the resin washed withdichloroethane (1 mL) (3×), then MeOH (1 mL) (2×). The resin was treatedwith 7N ammonia in MeOH (1 mL) for 30 min (2×) followed by filtrationand evaporation of solvent to give T2 (n=1, p=2, m=1, R²=H, R³=Me; R⁴=Buand R¹⁵=Ph and R¹⁶=H).

Method T, Step 2.

Procedure similar to Method Q, step 6 was used for the transformation ofT2 (n=1, p=2, m=1, R²=H, R³=Me; R⁴=iBu and R¹⁵=Ph and R¹⁵=H) to T3 (n=1,p=2, m=1, R²=H, R³=Me; R⁴==Bu and R¹⁵=Ph and R¹⁶=H).

The following compounds were prepared using similar methods: Obs. #Structure MW m/e 1333

348 349 1334

350 351 1335

350 351 1336

356 357 1337

362 363 1338

370 371 1339

384 385 1340

384 385 1341

400 401 1342

446 447 1343

448 449

Alternatively, similar synthetic method can be used for the generationof other types of compounds. i.e.

In a microwave vial was charged U1 (R²=H; R³=i-Bu, R⁴=Me) (0.025 g) intoluene (4 mL), potassium carbonate (0.035 g), Pd(dppf)Cl₂ (0.020 g).water (0.02 mL) and R²¹B(OH)₂ (R²¹=m-Methoxyphenyl) (3 eq.) were placed.The vial was placed in a microwave for 10 min. at 150° C. The reactionmixture was diluted with dichloromethane and extracted with 2.5N NaOH.The dried (MgSO₄) dichloromethane solution was concentrated in vacuo togive a brown residue which was purified via a RP Prep LCMS system togive product U2 (R²=H; R³=^(i)Bu: R⁴=Me; R²=m-methoxyphenyl).

The following compounds were prepared using similar methods: Obs. #Structure MW m/e 1344

279 280 1345

285 286 1346

293 294 1347

299 300 1349

299 300 1349

304 305 1350

309 310 1351

313 314 1352

318 319 1353

323 324 1354

323 324 1355

323 324 1356

329 330 1357

335 336 1358

335 336 1359

337 338 1360

343 344 1361

347 348 1362

347 348 1363

347 348 1364

347 348 1365

347 348 1366

349 350 1367

349 350 1368

350 351 1369

351 352 1370

352 353 1371

357 358 1372

359 360 1373

360 361 1374

360 361 1375

360 361 1376

360 361 1377

360 361 1378

360 361 1379

365 366 1380

365 366 1381

365 366 1382

365 366 1383

366 367 1384

371 372 1385

371 372 1386

371 372 1387

372 373 1388

372 373 1389

375 376 1390

377 378 1391

377 378 1392

377 378 1393

377 378 1394

379 380 1395

379 380 1396

380 381 1397

381 382 1398

383 384 1399

384 385 1400

385 386 1401

385 386 1402

386 387 1403

387 388 1404

389 390 1405

389 390 1406

392 393 1407

395 396 1408

403 404 1409

403 404 1410

405 406 1411

406 407 1412

413 414 1413

419 420 1414

497 498 1415

398 TBD 1416

399 TBD

Method V, Step 1:

Compound V1 (R³=R⁴=Me) (14.76 mmole), EDCI (14.76 mmole), HOAt mmole),and DIEA (14.76 mmole) were mixed with 36 ml DCM. This mixture wasstirred at RT for 15 min before 3-chlorobenzylamine was added. After thereaction solution was stirred at RT overnight, it was washed with sodiumcarbonate (3×), water, 1N HCl (4×), and aq sodium bicarbonate and driedover anhydrous sodium sulfate. The solvent was evaporated and theresidue was purified on flash column to give the amide product V2(R¹=3-chlorobenzyl; R³=R⁴=Me).

Method V, step 2

Compound V2 (R¹=3-chlorobenzyl; R³=R⁴=Me) (8.33 mmole) was dissolved in35 ml anhydrous DCM, and cooled to 0-5° C. Thiophosgene (9.16 mmole) in10 ml DCM was added dropwise under N₂ followed by addition of DIEA(11.96 mmole). The solution was stirred in ice bath for 0.5 h before thereaction mixture was washed with saturated sodium bicarbonate (3×),brine, and dried over anhydrous sodium sulfate. The solvent wasevaporated and residue purified on flash column usingethylacetate/hexane to give the thiohydantoin V3 (R¹=3-chlorobenzyl;R³=R⁴=Me).

Method V, step 3:

The thiohydantoin V3 (R¹=3-chlorobenzyl; R³=R⁴=Me) was treated witht-butyl hydroperoxide and ammonium hydroxide in MeOH at RT for 48 h togive compound V4 (R¹=3-chlorobenzyl; R²=H; R³=R⁴=Me).

The following compounds were prepared using similar method. Obs. Obs. #Structure MW m/e # Struture MW m/e 1417

251 252 1420

307 308 1418

265 266 1421

357 358 1419

293 294 1422

371 372

Compound W1 obtained using method A (n=1, R²=m-Cl-Bn, R³=Me) washydrolyzed to W2 (n=1, R²=m-Cl-Bn, R³=Me) using two equivalent of LiOHin MeOH.

The following compounds were synthesized in similar fashion: Obs. Obs. #Structure MW m/e # Structure MW m/e 1423

295 296 1426

411 412 1424

311 312 1427

425 426 1425

325 326

(In the scheme, -Z-NH—C(O)—N(R¹⁶)(R¹⁷)— is equivalent to R¹ substitutedby R²¹, or R¹ Subsitituted by alkyl-R²², wherein R²¹ and R²² are—NH—C(O)—N(R¹⁶)(R¹⁷) and R¹⁵ is H, and wherein Z is optionallysubstituted alkylene-arylene, alkylene-arylene-alkylene,alkylene-heteroarylene, alkylene-heteroarylene-alkylene,alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene,alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene,arylene, heteroarylene, cycloalkylene or heterocycloalkylene)

Method X, Step 1:

To a mixture of the amine X1 obtained using method L (R³=Me; R⁴=Bu;Z=para-(CH₂)C₆H₄(CH₂)—) (10 mg) in DCM and sat. NaHCO₃ (1:1 by volume)was added triphosgene (0.33 eq) at r.t. The solution was stirredvigorously for 40 minutes before the organic layer was separated anddried over anhydrous Na₂SO₄. The organic solution was evaporated to givecompound X2 (R³=Me; R⁴=i-Bu; Z=para-(CH₂)C₆H₄(CH₂)—).

Method X, Step 2:

Compound X3 (R¹⁵=H; R¹⁶=cyclopropylmethyl; R³=Me; R⁴=^(i)Bu;Z=para-(CH₂)C₆H₄(CH₂)—) was prepared from X2 (R³=Me; R⁴=i-Bu;Z=para-(CH₂)C₆H₄(CH₂)—) using method similar to method M, step 1.

Method X, Step 3:

Compound X4 (R¹⁶=H; R¹⁷=cyclopropylmethyl; R¹²=H; R³=Me; R⁴=^(i)Bu;Z=para-(CH₂)C₆H₄(CH₂)—) was prepared from X3 (R¹⁶=H;R¹⁷=cyclopropylmethyl; R²=H; R³=Me; R⁴=^(i)Bu; Z=para-(CH₂)C₆H₄(CH₂)—)using method similar to method A Step 3. NMR (CD₃OD): δ 7.25, s, 4H; δ4.8, m, 2H; δ 4.25, s, 2H; δ 2.9, m, 2H; δ 1.68, m, 2H; δ 1.44, m, 1H; δ1.36, s, 3H, δ 0.9, m, 1H; δ 0.82, m, 3H; δ 0.66, m, 3H; δ 0.4, m, 2H; δ0.12, m, 2H. ES_LCMS (m/e) 386.1.

The following compounds were prepared using a similar method. Obs. Obs.# Structure MW m/e # Structure MW m/e 1428

385 386 1443

518 519 1429

401 402 1444

518 519 1430

401 402 1445

524 525 1431

415 416 1446

524 525 1432

427 428 1447

526 527 1433

435 436 1448

532 533 1434

435 436 1449

533 534 1435

443 444 1450

537 538 1436

449 450 1451

537 538 1437

463 464 1452

545 546 1438

471 472 1453

559 560 1439

485 486 1454

570 571 1440

496 497 1455

572 573 1441

504 505 1456

598 599 1442

513 514

(In the scheme,

is equivalent to R¹ substituted by R², or R¹ Subsitituted by alkyl-R²²,wherein R²¹ and R²² are —N(R¹⁵)—C(O)—N(R¹⁶)(R¹⁷) and R¹⁵ and R¹⁶ form aring as defined above, and wherein Z is optionally substitutedalkylene-arylene, alkylene-arylene-alkylene, alkylene-heteroarylene,alkylene-heteroarylene-alkylene, alkylene-cycloalkylene,alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene,alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene,cycloalkylene or heterocycloalkylene)

Method Y, Step 1:

The reaction mixture of compound Y1 obtained from Method L (R³=Me;R⁴=i-Bu; Z=para-(CH₂)C₆H₄(CH₂)—) (0.1639 mmole), Y2 (R²³=H; R²³=Pr)(0.1967 mmole), PS-EDC resin (0.4917 mmole) and HOBT (0.2459 mmole) in3.5 ml of mixture of THF, MeCN and DMF (1:1:0.3) was shaken overnight atRT before 6 eq of PS-trisamine resin 3 eq of PS-isocyanate resin wereadded. After 6 hrs the reaction mixture was filtered and the resin waswashed with THF, DCM and MeOH. The combined filtrate was evaporated andthe crude was treated with 40% TFA in DCM for 40 min before the solventwas evaporated and residue purified on RP HPLC system to give product Y3(R³=Me; R⁴=i-Bu; Z=para-(CH₂)C₆H₄(CH₂)—, R²³=H; R²³=Pr).

Method Y, Step 2:

The reaction solution of Y3 (R³=Me; R⁴=i-Bu; Z=para-(CH₂)C₆H₄(CH₂)—,R²³=H; R²³=Pr) (0.030 mmole), carbonyl diimidazole (0.032 mmole), andDIEA (0.09 mmole) in 0.5 ml DCM was shaken overweekend at RT. The crudewas then purified on reverse column to give the thiohydantoin productwhich was converted into Y4 (R²=H; R³=Me; R⁴=^(i)Bu;Z=para-(CH₂)C₆H₄(CH₂)—, R²³=H; R²³=Pr).

The following compounds were prepared using similar method. Obs. Obs. #Structure MW m/e # Structure MW m/e 1457

413 414 1459

427 428 1458

413 414

(In the scheme, -Z-NH—C(O)—N(R¹⁶)(R¹⁷)— is equivalent to R¹ substitutedby R²¹, or R¹ Subsitituted by alkyl-R²², wherein R²¹ and R²² are—N(R¹⁵)—C(O)—N(R¹⁶)(R¹⁷) and R¹⁵ is H, and wherein Z is optionallysubstituted alkylene-arylene, alkylene-arylene-alkylene,alkylene-heteroarylene, alkylene-heteroarylene-alkylene,alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene,alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene,arylene, heteroarylene, cycloalkylene or heterocycloalkylene)

Method Z, Step 1:

To the solution of the Phoxime™ resin (1.23 mmol/g) in DCM was added theamine Z1 obtained from method L (R³=Me; R⁴=^(i)Bu;Z=para-(CH₂)C₆H₄(CH₂)—) (2 eq). The mixture was shaken overnight beforethe resin was filtered and washed with DCM, MeOH, THF (3 cycles), thenDCM (×2), dried in vacuum to get resin Z2 (R³=Me; R⁴=Bu;Z=para-(CH₂)C₆H₄(CH₂)—).

Method Z, Step 2:

To the resin Z2 (R³=Me; R⁴=¹Bu; ==para-(CH₂)C₆H₄(CH₂)—), swelled in DCM,in toluene was added N-methylbenzylamine (4 eq). The mixture was heatedat 80-90° C. overnight before MP-TSOH resin (1.3 mmol/g, 12 eq) wasadded. The mixture was shaken for 1.5 hours, the solution was filteredand the resin washed with DCM and MeOH. The combined organic solutionwas concentrated in vacuo to get Z3 (R³=Me; R⁴=^(i)Bu;Z=para-(CH₂)C₆H₄(CH₂)—; R¹⁶=Me; R¹⁷=Bn).

Method Z, Step 3:

Compound Z4 (R³=Me; R⁴=^(i)Bu; Z=para-(CH₂)C₆H₄(CH₂)—; R¹⁶=Me; R¹⁷=Bn)was generated from Z3 (R³=Me; R⁴=^(i)Bu; Z=para-(CH₂)C₆H₄(CH₂)—; R¹⁶=Me;R¹⁷=Bn) using method similar to Method A step 3.

The following compounds were prepared using similar method. Obs. Obs. #Structure MW m/e # Structure MW m/e 1460

457 458 1474

531 532 1461

469 470 1475

533 534 1462

471 472 1476

533 534 1463

471 472 1477

538 539 1464

483 484 1478

545 546 1465

485 486 1479

547 548 1466

485 486 1480

547 548 1467

495 496 1481

547 548 1468

499 500 1482

551 552 1469

501 502 1483

568 569 1470

507 508 1484

571 572 1471

509 510 1485

593 594 1472

517 518 1486

596 597 1473

517 518 1487

607 608 1488

364 365 1489

377 377 1490

513 514

8,11-Dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (AA2)(18 mg) was reacted with AA1, obtained from method Q, anddiisopropylethylamine (14 uL) in acetonitrile (2.5 mL). The resultingmixture was heated at 65° C. for 18 h. The reaction mixture was placedon a preparative silica gel plate and eluted with hexane:ethyl acetate3:1 to give the desired product which was treated with 40% TFA.Evaporation of the solvent followed by purification afforded compoundAA3.

The following compounds were prepared by similar methods: Obs. Obs. #Structure MW m/e # Structure MW m/e 187

491 492 188

493 494

Method AB, Step 1:

To a solution of (R)-(+)-2-methyl-2-propane sulfinamide (1.0 g, 8.3mmol, 1 eq) and AB1 (R⁶=Ph, R⁷=n-Bu) (3 mL, 9.1 mmol, 1.1 eq) inanhydrous THF (30 mL) at room temperature was added Ti(OEt)₄ (7 mL, 17mmol, 2 eq). The mixture was heated at 70° C. for 24 h. After cooling toroom temperature, the mixture was poured into 30 mL of brine undervigourous stirring. The resulting suspension was filtered through a padof Celite and the solid was washed with EtOAc (2×20 mL). The filtratewas washed with brine (30 mL), dried (Na₂SO₄), and concentrated invacuo. The residue was chromatographed on silica by eluting withhexane/Et₂O (5:1) to give 1.9 g (85%) of(R)-2-methyl-N-(1-phenylpentylidene)propane-2-sulfinamide. ¹HNMR (CDCl₃,300 MHz): δ 7.91 (m, 2H), 7.52-7.37 (m, 3H), 3.27 (m, 1H), 3.15 (m, 1H),1.73-1.61 (m, 2H), 1.47-1.38 (m, 2H), 1.31 (s, 9H), 0.95 (m, 3H). MS(ESI): MH⁺=265.9. HPLC t_(R)=7.24, 7.58 min (E/Z=5.5:1).

To a solution of methyl acetate (0.6 mL, 6.9 mmol, 2 eq) in THF (5 mL),LDA (2M in heptane/THF, 3.4 mL, 6.9 mmol, 2 eq) was added dropwise via asyringe at −78° C. After stirring at −78° C. for 30 min, a solution ofClTi(Oi-Pr)₃ (1.8 mL, 7.6 mmol, 2.2 eq) in THF (5 mL) was addeddropwise. After stirring for another 30 min, a solution of(R)-2-methyl-N-(1-phenylpentylidene)propane-2-sulfinamide (0.9 g, 3.4mmol, 1 eq) in THF (2 mL) was added dropwise via a syringe. The mixturewas stirred at −78° C. for 3 h and TLC showed no starting material left.A saturated aqueous solution of NH₄Cl (10 eq) was added and thesuspension was warmed to room temperature. The mixture was diluted withH₂O (50 mL) and stirred for 10 min. The mixture was then partitionedbetween H₂O (50 mL) and EtOAc (50 mL). The organic layer was separatedand the aqueous layer was extracted with EtOAc (3×50 mL). The combinedorganic layers were washed with brine, dried (MgSO₄) and concentrated togive 1.1 g of a brown oil. Chromatography on silica gel using 50%EtOAc/hexanes as eluent gave 0.8 g (76%) of methyl3-((R)-2-methylpropan-2-ylsulfinamido)-3-phenylheptanoate as a yellowoil. ¹HNMR (CDCl₃, 300 MHz): 87.15-7.07 (m, 5H), 3.35 (s, 1H), 3.19 (dd,J=16, 5.6 Hz, 1H), 3.01 (dd, J=15.8, 5.5 Hz, 1H), 2.07 (m, 2H), 1.71 (m,2H), 1.35-1.26 (m, 4H), 1.17 (s, 9H), 0.89 (m, 3H). MS (ESI): MH⁺=339.9.HPLC t_(R)=7.50, 7.6 min (E/Z=1.5:1)

To a solution of methyl3-((R)-2-methylpropan-2-ylsulfinamido)-3-phenylheptanoate (0.4 g, 1.1mmol) in 12 mL of MeOH was added 16 mL of 4N HCl/dioxane. After stirringfor 30 min, the volatiles were removed in vacuo. The residue wasre-dissolved in MeOH (6 mL), stirred for 5 min, and evaporated again toafford 0.30 g (97%) of AB2 (R⁶=Ph, R⁷=n-Bu) as a yellow solid. ¹HNMR(CDCl₃, 300 MHz): 69.01 (brs, 2H), 7.37-7.12 (m, 5H), 3.64 (m, 1H), 3.54(s, 3H), 3.31 (m, 1H), 2.09 (m, 2H), 1.8 (m, 2H), 1.1 (m, 4H), 1.07 (s,9H), 0.7 (m, 3H). MS (ESI): MH⁺=235.9. HPLC t_(R)=4.72 min.

Method AB, Step 2:

Treatment of compound AB2 (R⁶=Ph, R⁷=n-butyl) with thiophosgene inCH₂Cl₂ in the presence of aqueous NaHCO₃ at 0° C. generatesisothiocyanate AB3 (R⁶=Ph, R⁷=n-butyl) which was converted into finalproduct using method similar to Method A Step 2 and Method A Step 3 togive product AB5 (R⁶=Ph, R⁷=n-butyl, R¹=Me). ¹HNMR (CDCl₃, 300 MHz): δ10.4 (brs, 1H), 7.25-7.11 (m, 5H), 3.23 (dd, J=16, 5.6 Hz, 1H), 3.03 (s,3H), 2.8 (dd, J=15.8, 5.5 Hz, 1H), 2.49 (s, 1H), 1.78 (m, 2H), 1.1-1.0(m, 4H), 0.99 (m, 3H). MS (ESI): MH⁺=260.2. HPLC t_(R)=5.09 min.

The following compounds were synthesized using similar methods: Obs. Obs# Structure MW m/e # Structure MW m/e 189

239 240 195

443 444 190

253 254 196

463 464 191

259 260 197

537 538 192

333 334 198

537 538 193

333 334 199

295 296 194

349 350 200

295 296

The synthesis was adapted from a procedure by Hull, R. et al, J. Chem.Soc. 1963, 6028-6033. Thus, to a solution of AC2 (R¹=Benzyl) (0.72 g,5.9 mmol) in AC1 (R⁴=Me, R³=Me) (1.4 mL) was added a 50% aqueoussolution of cyanamide (0.31 mL, 8.0 mmol). The reaction was heated withstirring at reflux (˜40° C.) for 0.5 h, then cooled to 25° C. andstirred for an additional 16 h. The volatiles were removed in vacuo andthe residue was partitioned between ether and H₂O. The organic layer wasdried over Na₂SO₄, filtered and the volatiles were removed in vacuo. Theresidue was purified by column chromatography using 5-10% CH₃OH/CH₂Cl₂as eluent followed by reverse phase preparative HPLC to give 0.15 g(8.0%) of AC3 (R¹=benzyl, R⁴=Me and R³=Me) as a white solid. ¹H NMR(CH₃OH, 300 MHz): 87.35-7.33 (m, 5H), 4.71 (s, 2H), 1.46 (s, 6H); ¹³CNMR (CDCl₃, 75 MHz) δ 157.8, 135.6, 129.1, 128.5, 127.9, 104.2, 59.6,28.8. MS (ESI) m/e 206.1 (M⁺H)⁺. # Structure MW Obs. m/e 201

205 206

Method AD, Step 1:

AD2 (R³=Ph, R⁴=^(t)Butyl) was prepared from AD1 using method similar toMethod AB, step 2.

Method AD, Step 2:

The synthesis was adapted from a procedure by Hussein, A. Q. et al,Chem. Ber. 1979, 112, 1948-1955. Thus, to a mixture of AD2 (R³=Ph,R⁴=tert-Butyl) (0.56 g, 2.7 mmol) and boiling chips in CCl₄ (25 mL) wasadded N-bromosuccinimide (0.49 g, 2.7 mmol). The mixture was irradiatedwith a 200 watt light source for 1 h. The reaction was cooled, the solidfiltered off and the volatiles were removed in vacuo. Chromatography onsilica gel by eluting with 5% EtOAc/hexane gave 0.57 g (73%) of1-(1-bromo-1-isothiocyanato-2,2-dimethylpropyl)benzene as a beigepowder. ¹H NMR (CDCl₃, 300 MHz): δ 7.63-7.61 (m, 2H), 7.37-7.26 (m, 3H),1.17 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 139.1, 129.0, 128.9, 128.6,127.5, 91.2, 45.6, 26.6. MS (ESI) m/e 284.9 (M⁺H)⁺.

To a solution of 1-(1-bromo-1-isothiocyanato-2,2-dimethylpropyl)benzene(0.13 g, 0.47 mmol) and the hydrochloride salt of N-methylhydroxylamine(0.047 g, 0.57 mmol) in THF (3 mL) was added triethylamine (0.18 mL,1.32 mmol). The mixture was stirred at 25° C. for 16 h, filtered and thevolatiles were removed in vacuo. The residue was purified by columnchromatography using CH₃OH/CH₂Cl₂ as eluent to give 0.050 g (42%) of AD3(R³=Ph, R⁴=tert-Butyl) as a glassy solid. ¹H NMR (CDCl₃, 300 MHz): δ7.35-7.26 (m, 5H), 3.38 (s, 3H), 1.0 (s, 9H); MS (ESI) m/e 251.1 (M⁺H)⁺.

Method AD, Step 3:

To a solution of AD3 (R³=Ph, R⁴=tert-Butyl) (0.065 g, 0.26 mmol) inCH₃OH (5 mL) at 0° C. was added a solution of aqueous ammonia (2 mL)followed by a 70% aqueous solution of t-butylhydroperoxide (2 mL). Thereaction was allowed to warm to 25° C. and stirred for 16 h, Thevolatiles were removed and the residue was purified by reverse phaseHPLC to give 2.0 mg (2.2%) of AD4 (R³=Ph, R⁴=tert-Butyl) as a colorlessoil. ¹H NMR (CDCl₃, 300 MHz) δ 7.47-7.43 (m, 2H), 7.39-7.35 (m, 3H),3.23 (s, 3H), 1.0 (s, 9H); MS (ESI) m/e 234.2 (M⁺H)⁺.

The following compounds were synthesized using similar methods: Obs.Obs. # Structure MW m/e # Structure MW m/e 202

213 214 204

309 310 203

233 234

Method AE, Step 1:

TBDMS-CI (5.3 g, 35.19 mmole) and imidazole (2.4 g, 35.19 mmole) wereadded to a suspension of H2 (R¹=Me, R³=cyclohexylmethyl) (8.2 g, 31.99mmole) in 220 ml DCM. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was filtered, and thefiltrate was diluted with 1200 ml EtOAc. The organic phase was washedwith saturated NaHCO₃ 3× and brine 3×, and dried over anhydrous Na₂SO₄to give 12 g of AE2 (R¹=Me, R³=cyclohexylmethyl), which was used fornext step without further purification.

Method AE, Step 2:

AE2 (R¹=Me, R³=cyclohexylmethyl; 12 grams crude) was converted toiminohydantoin using conditions similar to Method A Step 3, which wassubsequently treated with 75% TFA in DCM at room temperature for 24 hrs.The solvent was evaporated in vacuo to give 13.6 g of a product that wasreacted with Boc anhydride to give 5.8 g AE3 (R¹=Me,R³=cyclohexylmethyl) after column purification.

Method AE, Step 3:

AE4 (R¹=Me, R³=cyclohexylmethyl) (8.2 g) was obtained from AE3 (5.8 g)according to the step 4 of the method H.

Method AE, Step 4:

To a solution of AE4 (R¹=Me, R³=cyclohexylmethyl) ((3.95 g, 8.38 mmol)in anhydrous THF (98 mL) was added diisopropylethylamine (7 mL, 40mmol). The reaction was stirred under N₂ (gas) at room temperature.After 5.5 h, the reaction was concentrated and the crude material waspurified via flash chromatography eluting with a gradient of 0 to 75%ethyl acetate in hexane to afford AE5 (R¹=Me, R³=cyclohexylmethyl) (2.48g, 92%).

Method AE, Step 4:

To a solution of R¹⁵OH(R¹⁵=cyclobutyl) (10 μl) and HBF₄ (1 equiv) inanhydrous methylene chloride (0.5 mL) was added a solution of AE5(R¹=Me, R³=cyclohexylmethyl) (20 mg, 0.062 mmol) in methylene chloride(0.5 mL). The reaction was agitated overnight at rt. Trifluoroaceticacid (1 mL) was added to the reaction mixture and the solution wasagitated for 1 h at rt. The reaction was concentrated and the crudematerial was purified via reverse phase preparative HPLC/MS eluting witha 7 min gradient of 5 to 95% CH₃CN in H₂O with 0.1% formic acid toafford AE5 (R¹=Me, R³=cyclohexylmethyl, R¹⁵=cyclobutyl).

The following compounds were synthesized using similar method: Obs. Obs.# Structure MW m/e # Structure MW m/e 205

267 268 226

335 336 206

293 294 227

335 336 207

295 296 228

335 336 208

295 296 229

335 336 209

295 296 230

335 336 210

295 296 231

335 336 211

305 306 232

335 336 212

307 308 233

337 338 213

307 308 234

337 338 214

309 310 235

349 350 215

309 310 236

349 350 216

309 310 237

349 350 217

309 310 238

349 350 218

321 322 239

353 354 219

321 322 240

361 362 220

321 322 241

363 364 221

322 323 242

363 364 222

329 330 243

363 364 223

333 334 244

389 390 224

335 336 245

321 NA 225

335 336

To a solution of tBuOK (9.5 mg, 0.0848 mmole) in 0.5 ml anhydrous THFwas added ArOH (Ar=m-Chlorophenyl)(13 μl, 0.1273 mmole) in 0.5 mlanhydrous THF followed by addition of AE4 (R¹=Me, R³=cyclohexylmethyl)(20 mg, 0.0424 mmole) in 0.5 ml anhydrous THF. The reaction mixture wasstirred at room temperature for 2 days before it was diluted with 1 mlMeCN, treated with 100 mg MP-TsOH resin and 100 mg Amberlyst A26 resin.The resin was removed by filtration and the filtrate was evaporated downto give a product that was treated with 50% TFA for 1 hr. Afterevaporation of TFA in vacuo, the residue was dissolved in 2 ml MeCN, andtreated with 100 mg MP-TsOH resin. The resin was washed thoroughly withTHF, MeCN and MeOH, and then treated with 2M NH₃ in MeoH to give AF2(R¹=Me, R³=cyclohexylmethyl and R¹⁵=3-chlorophenyl).

The following compounds were synthesized using similar method: Obs. Obs.# Structure MW m/e # Structure MW m/e 246

316 317 309

365 366 247

316 317 310

365 366 248

316 317 311

366 367 249

329 330 312

366 367 250

329 330 313

366 367 251

329 330 314

366 367 252

330 331 315

366 367 253

331 332 316

366 367 254

331 332 317

366 367 255

333 334 318

367 368 256

333 334 319

367 368 257

333 334 320

367 368 258

333 334 321

369 370 259

333 334 322

371 372 260

340 341 323

371 372 261

340 341 324

371 372 262

340 341 325

372 373 263

343 344 326

372 373 264

343 344 327

372 373 265

343 344 328

372 373 266

343 344 329

373 374 267

344 345 330

373 374 268

344 345 331

375 376 269

345 346 332

375 376 270

345 346 333

375 376 271

345 346 334

377 378 272

345 346 335

377 378 273

347 348 336

377 378 274

347 348 337

383 384 275

349 350 338

383 384 276

349 350 339

383 384 277

349 350 340

383 384 278

349 350 341

383 384 279

351 352 342

383 384 280

351 352 343

383 384 281

351 352 344

383 384 282

351 352 345

383 384 283

351 352 346

383 384 284

351 352 347

385 386 285

351 352 348

385 386 286

351 352 349

386 387 287

355 356 350

387 388 288

355 356 351

387 388 289

357 358 352

393 394 290

357 358 353

393 394 291

357 358 354

393 394 292

357 358 355

393 394 293

358 359 356

399 400 294

358 359 357

399 400 295

358 359 358

400 401 296

358 359 359

400 401 297

359 360 360

400 401 298

359 360 361

401 402 299

359 360 362

401 402 300

359 360 363

401 402 301

359 360 364

405 406 302

360 361 365

411 412 303

360 361 366

414 415 304

360 361 367

417 418 305

363 364 368

417 418 306

363 364 369

421 422 307

363 364 370

434 435 308

363 364 371

451 452

Method AG, Step 1:

R²¹-H (R²¹=PhS—) (33 μl, 0.318 mmole) was treated with NaH (10.2 mg, 60%in mineral oil) in 0.5 ml anhydrous THF. A solution of AE4 (R¹=Me,R³=Cyclohexylmethyl) (20 mg, 0.0424 mmol) in 0.5 ml anhydrous THF wasadded. The reaction mixture was stirred at room temperature overnightbefore it was partitioned between ether and saturated NaHCO₃ watersolution. The aqueous phase was extracted with ether 2 times. Thecombined organic phase was washed with brine 2 times, and dried overanhydrous NaSO₄. The crude was purified on flash column withEtOAc/hexane to give 9 mg of AG1 (R²¹=PhS—, R¹=Me, R³=cyclohexylmethyl)(49.2% yield).

Method AG, Step 2:

AG1 (R²¹=PhS—, R¹=Me, R³=cyclohexylmethyl) was treated with 50% TFAaccording to the Step 6 of the method H to give AG2 (R²¹ =PhS—, R¹=Me,R³=cyclohexylmethyl).

The following compounds were synthesized using similar method: Obs. Obs.# Structure MW m/e # Structure MW m/e 372

315 316 374

337 338 373

331 332

Method AH, Step 1:

Benzophenone imine (3.27 g, 18.04 mmole) was added to a suspension ofAH1 (R³=cyclohexylmethyl) (4 g, 18.04 mmole) in 65 ml DCM. The reactionmixture was stirred at room temperature overnight under N₂ before thesolid was filtered, and the solvent was evaporated. The residue wasdissolved in 100 ml ether, washed with water 2× and dried over anhydrousMgSO₄. The crude was purified on flash column to give 5.08 g (80.57%yield) of AH2 (R³=cyclohexylmethyl).

Method AH, Step 2:

A solution of AH2 (R³=cyclohexylmethyl) (1 g, 2.86 mmole) in 12 mlanhydrous THF was added to a suspension of 18-crown-6 (0.76 g, 2.86mmole) and 30% KH in mineral oil (1.16 g, 8.58 mmole) in 4 ml anhydrousTHF under N2. The mixture was cooled in ice-bath and R⁴Br(R⁴=3-pyridylmethyl, as a hydrobromide salt) was then added. Thereaction mixture was stirred in ice-bath for 30 min and at roomtemperature for 2 more hrs before the reaction was quenched with 2 ml ofHOAc/THF/H₂O (0.25:0.75:1). The mixture was diluted with 40 ml EtOAc/H₂O(1:1). The aqueous phase was extracted with EtOAc 3 times. The combinedorganic phase was washed with brine 3 times and dried over anhydrousMgSO4. The crude was purified on flash column to give 0.44 g (35.14%yield) of product which was treated with 1N HCl (2.2 ml, 2.22 mmole) in3 ml ether in ice-bath followed by stirred at r.t. overnight. Theaqueous phase was evaporated and purified on C-18 reverse phase columnto give 0.22 g (66% yield) of AH3 (R⁴=3-pyridylmethyl;R³=cyclohexylmethyl).

To a solution of compound AI1 (R¹=Me, R³=n-Bu) (34 mg, 0.105 mmol) inmethanol (1 ml) was added 10% Pd/C (5 mg). The mixture was kept under anH₂ balloon for 1 hr. After filtration of the catalyst, the filtrate wasconcentrated to get crude product. This residue was purified by RP HPLCto get compound A12 (R¹=Me, R³=n-Bu) (25 mg, 100%). Observed MW (M⁺H)246.1; exact mass 245.15. ¹H NMR (400 MHz, CD₃OD): δ=7.59 (m, 2H), 7.36(m, 3H), 3.17 (s, 3H), 2.17 (m, 2H), 1.27 (m, 4H), 0.86 (t, 3H, J=7.2Hz).

The following compounds were synthesized using similar method: Obs. Obs.# Structure MW m/e # Structure MW m/e 375

283 284 380

463 464 376

285 286 381

487 488 377

299 300 382

489 490 378

450 451 383

503 504 379

462 463 384

516 517

To a mixture of compound AJ1 (R¹=Me, R³=n-Bu) (70 mg, 0.165 mmol) andbutylzincbromide (1.32 ml, 0.6 mmol) was added Pd(dppf)Cl₂. The mixturewas degassed, sealed and heated at 55° C. for 1 day. The mixture wasdiluted with CH₂Cl₂ and NH₃/H₂O. The organic layer was separated, dried,concentrated, and purified by RP HPLC to get product which was thentreated with 4N HCl/dioxane for 30 min to give compound AJ2(R¹=Me,R³=n-Bu) (12 mg, 25%). Observed MW (M⁺H) 302.1; ¹H NMR (400 MHz, CD₃OD):δ=7.32 (m, 3H), 7.22 (m, 1H), 3.19 (s, 3H), 2.65 (m, 2H), 2.20 (m, 2H),1.60 (m, 2H), 1.38 (m, 4H), 1.24 (m, 2H), 0.92 (m, 6H).

The following compound was synthesized in a similar fashion: Obs. Obs. #Structure MW m/e # Structure MW m/e 386

518 519 385

301 302

To a solution of AK1 (R¹=Me, R³=n-Butyl, R²¹=n-Bu) (9 mg, 0.03 mmol) inmethanol (1 ml) was added 5% Pt/C (5 mg), Rh/C (5 mg) and conc. HCl(0.05 ml). The mixture was kept under H₂ (50 psi) for 2 days. After thefiltration of the catalyst, the filtrate was concentrated to getcompound AK2 (R¹=Me, R³=n-butyl, R²¹=n-Bu) Observed MW (M⁺H) 308.1. ¹HNMR (CD₃OD): δ=3.16 (s, 3H), 1.80 (m, 6H), 1.26 (m, 16H), 0.88 (m, 6H).

The following compounds were synthesized using similar method: Obs. Obs.# Structure MW m/e # Structure MW m/e 387

277 278 391

391 392 388

291 292 392

391 392 389

305 306 390

307 308

Method AL, Step 1:

To a solution of compound AL1 (R³=n-Bu) (418 mg, 1.39 mmol) in methanol(8 ml) was added PtO₂ (40 mg) and conc. HCl (0.4 ml). The mixture washydrogenated (50 psi) for 1 day. After filtration of the catalyst, thefiltrate was concentrated. The crude residue was basified to pH=11-12 by1N NaOH. This mixture was extracted with ethyl acetate. The organiclayer was separated, dried and concentrated to get compound AL2(R³=n-Bu) (316 mg, 100%).

Method AL, Step 2:

To a solution of compound AL2 (R³=n-Bu) (300 mg, 1.32 mmol) indichloromethane (6 ml) was added (BOC)₂O (316 mg, 1.45 mmol). Themixture was stirred at RT for 1.5 hr. It was diluted with water anddichloromethane. The organic layer was separated, dried and concentratedto get compound AL3 (R³=n-Bu) (464 mg, 100%).

Method AM, Step 1:

Compound AM1 (R¹=Me, R³=n-Butyl) was treated with 4N HCl in dioxane for2 hr. The mixture was concentrated to get compound AM2 as an HCl salt(R¹=Me, R³=n-Butyl). Observed MW (M⁺H) 470.1; ¹H NMR (CD₃OD): δ=7.28 (m,2H), 6.96 (m, 3H), 4.80 (m, 2H), 4.56 (m, 1H), 4.00 (m, 1H), 3.64 (m,4H), 3.37 (m, 2H), 3.12 (m, 1H), 3.00 (m, 1H), 2.90 (m, 1H), 2.72 (m,1H), 2.38 (m, 1H), 2.12-1.62 (m, 8H), 1.35 (m, 6H), 1.12 (m, 1H), 0.91(m, 3H).

Method AM, Step 2:

To a solution of compound AM2 (R¹=Me, R³=n-Butyl) (32 mg, 0.068 mmol) indichloromethane (1 ml) was added acetyl chloride (5 ul, 0.072 mmol). Themixture was stirred for 2 hr. It was then diluted with CH₂Cl₂ and water.The organic layer was separated, dried, concentrated and purified by RPHPLC to get compound AM3 (R¹=Me, R³=n-Butyl and R¹⁵=Me) Observed MW(M⁺H) 512.3; ¹H NMR (400 MHz, CDCl₃): δ=7.27 (m, 2H), 6.98 (m, 1H), 6.92(m, 2H), 4.65 (s, 2H), 4.50 (m, 2H), 3.98 (m, 1H), 3.70 (m, 1H), 3.41(m, 2H), 2.98 (m, 2H), 2.62 (m, 1H), 2.50 (m, 1H), 2.47 (m, 1H), 2.02(m, 5H), 1.75 (m, 6H), 1.26 (m, 7H), 0.84 (m, 3H).

The following compounds were synthesized using similar method: Obs. Obs.# Structure MW m/e # Structure MW m/e 394

252 253 397

469 470 395

252 253 398

498 499 396

456 457 399

511 512

To a solution of compound AN2(R¹=4-N-(α-phenoxyacetyl)piperidinylmethyl, R3=n-Butyl) (28 mg, 0.06mmol) in dichloroethane (2 ml) was added butyraldehyde (5.3 ul, 0.06mmol), triethylamine (8.4 ul, 0.06 mmol) and NaBH(OAc)₃ (18 mg, 0.084mmol). The mixture was stirred overnight. It was then diluted withdichloromethane and water. The organic layer was separated, dried,concentrated and purified by RP HPLC to get AN2(R¹=4-N-(α-phenoxyacetyl)piperidinylmethyl, R³=n-Butyl, R¹⁵=propyl andR¹⁶=H) (5.4 mg, 17%). Observed MW (M⁺H) 526.1; exact mass 525.37. ¹H NMR(CD₃OD): δ=7.28 (m, 2H), 6.96 (m, 3H), 4.76 (m, 2H), 4.55 (m, 1H), 4.05(m, 1H), 3.77 (m, 1H), 3.61 (m, 3H), 3.50 (m, 1H), 3.11 (m, 4H), 2.85(m, 1H), 2.68 (m, 1H), 2.38 (m, 1H), 2.05 (m, 2H), 1.95 (m, 2H), 1.73(m, 5H), 1.39 (m, 8H), 1.10 (m, 1H), 0.99 (m, 3H), 0.92 (m, 3H).

The following compound was synthesized using similar method: Obs. Obs. #Structure MW m/e # Structure MW m/e 400

308 309 402

525 526 401

308 309

A mixture of copper chloride (2.06 g, 20.8 mmol) and lithium chloride(1.76 g, 41.6 mmol) in 100 ml of THF was cooled down to −78° C. To thismixture, a 2.0M solution of AO1 (R³=n-butyl) (10 ml, 20 mmol) was addedgradually. The reaction was warmed up to −60° C., and AO2 (R⁴=m-Br—Ph)(2.9 ml, 22 mmol) was injected. The mixture was stirred at −60° C. for15 minutes and then quickly warmed up to RT by removing the dry-icebath. The reaction was quenched with water and sat. NaHCO₃. Afteraddition of diethyl ether, a lot of precipitate formed and was filtered.From the biphasic filtrate, the organic layer was separated, dried,concentrated and purified by silica gel chromatography (10%EtOAc/hexane) to get ketone AO3 (R⁴=m-BrPh, R³=n-Bu) (3.93 g, 82%).Observed MW (M⁺H) 241.1; exact mass 240.01. ¹H NMR (400 MHz, CDCl₃):δ=8.07 (m, 1H), 7.88 (m, 1H), 7.64 (m, 1H), 7.34 (m, 1H), 2.94 (t, 3H,J=7.2 Hz), 1.71 (m, 2H), 1.40 (m, 2H), 0.95 (t, 3H, J=7.6 Hz).

The following ketones were made according to Method 9: Observed MWStructure (M + H) Exact mass

242.1 241.01

Method AP, Step 1:

To a solution of AP1 (R⁴=3-Bromophenyl) (5 g, 25 mmol) indichloromethane (10 ml) were added N,O-dimethylhydroxylaminehydrochloride (2.56 g, 26.25 mmol) and 4-methylmorpholine (2.95 ml,26.25 mmol). EDCI (5.04 g, 26.25 mmol) was then added portionwise. Thereaction mixture was stirred at RT overnight and was then quenched with1N HCl (60 ml). The mixture was extracted with dichloromethane. Theorganic layer was washed with 1N HCl and brine, dried over Na₂SO₄, andconcentrated to give the Weinreb amide AP2 (R⁴=m-Bromophenyl) (5.96 g,98%). Observed MW (M⁺H) 244.1; exact mass 243.99. ¹H NMR (CDCl₃): δ=7.78(m, 1H), 7.58 (m, 2H), 7.24 (m, 1H), 3.51 (s, 3H), 3.32 (s, 3H). Thismaterial was used in the next step without purification.

Method AP, Step 2:

To a suspension of magnesium turnings (1.19 g, 48.8 mmol) in 30 ml ofTHF was added dropwise a solution of R³Br (R³=cyclohexylethyl) (5.73 ml,36.6 mmol) in 24 ml of THF. After addition of half of the solution ofbromide, several crystals of iodine were added to initiate the reaction.The mixture became cloudy and heat evolved. The rest of the solution ofbromide was added dropwise. The mixture was stirred at RT for 30 minutesand then was cooled to 0° C., and the AP2 (R⁴=m-Bromophenyl) (5.96 g,24.4 mmol) was added. The mixture was stirred at RT for 3 hr and thenquenched with 1N HCl until no residual Mg(0) was left. The phases wasseparated, and the water layer was extracted with ether. The combinedorganic layers were washed with brine, dried, and concentrated. Thecrude was purified by silica chromatography (15% EtOAc/hexane) to getketone AP3 (R⁴=m-Bromophenyl, R³=Cyclohexylethyl) (8.06 g, 100%).Observed MW (M⁺H) 295.2; exact mass 294.06. ¹H NMR (400 MHz, CDCl₃):δ=8.18 (m, 1H), 7.85 (m, 1H), 7.64 (m, 1H), 7.33 (m, 1H), 2.94 (t, 3H,J=7.2 Hz), 1.70 (m, 9H), 1.63 (m, 4H).

To a −78° C. solution of AQ1 (R⁴=cyclopropyl) (2.55 g, 38.0 mmol) indiethyl ether (100 ml) was added AO3 (R³=n-Bu) (38 ml, 1.5 M in hexanes,57 mmol). After 45 min, the cooling bath was removed. After 3 h at RT,the reaction was quenched by dropwise addition of water and then dilutedfurther with EtOAc and water. The phases were separated and the aqueouslayer was extracted with EtOAc (2×). The organic portions were combined,washed with brine, dried over MgSO₄, and concentrated. This cruderesidue was subjected to column chromatography (silica gel, 0%→100%CH₂Cl₂/hexanes) to provide the desired ketone AQ4 (R⁴=cyclopropyl,R³=n-Butyl) (2.57 g, 20.4 mmol, 54%). ¹H NMR (CDCl₃) δ 2.52 (t, J=7.2Hz, 2H), 1.90 (m, 1H), 1.57 (m, 2H), 1.30 (m, 2H), 0.98 (m, 2H), 0.89(t, J=7.6 Hz, 3H), 0.83 (m, 2H).

Method AR:

Compound B2 (R¹=m-Cl-Phenethyl, R³=Me, R⁴=i-butyl and R⁵=benzyl) wasconverted into AR2 (R¹=m-Cl-Phenethyl, R³=Me, R⁴=i-butyl and R⁵=benzyl)using method A step 3.

The following compounds were synthesized using similar methods: Obs.Obs. # Structure MW m/e # Structure MW m/e 403

396 397 407

340 NA 404

354 NA 408

382 NA 405

477 NA 409

446 NA 406

460 NA

Method AS, Step 1:

To a mixture of AS1 (R³=Ph) (3.94 g) in toluene (10 ml) was addedthionyl chloride (1.61 ml) and the resulting mixture as heated underreflux for 6 h (until HCl evolution ceased). The reaction mixture waskept overnight at rt before it was concentrated in vacuo. Toluene (10ml) was added and the mixture was concentrated in vacuo again. Thereaction mixture was dissolved in CH₂Cl₂, solid sodium bicarbonateadded, filtered and then the CH₂Cl₂ solution was concentrated in vacuoto give AS2 (R³=Ph).

Method AS, Step 2:

To AS2 (R³=Ph) (0.645 g) and AS5 (R⁴=4-chlorophenyl) (0.464 g), and1,3-dimethylimidazolium iodide (0.225 g) in anhydrous THF (20 ml) wasadded 60% sodium hydride in oil (0.132 g). The resulting mixture wasstirred at rt for 18 h. The reaction mixture was concentrated andpartitioned between H₂O and Et₂O. The dried Et₂O solution wasconcentrated in vacuo to give a yellow residue which was placed onpreparative silica gel plates and eluted with CH₂Cl₂ to give AS3 (R³=Ph,R⁴=p-ClPh). (Miyashita, A., Matsuda, H., Hiagaskino, T., Chem. Pharm.Bull., 1992, 40 (10), 2627-2631).

Method AS, Step 3:

Hydrochloric acid (1N, 1.5 ml) was added to AS3 (R³=Ph, R⁴=p-ClPh) inTHF (10 ml) and the resulting solution was stirred at rt for 20 h. Thereaction mixture was concentrated in vacuo and then partitioned betweenCH₂Cl₂ and H₂O. The dried CH₂Cl₂ was concentrated in vacuo to give aresidue which was placed on preparative silica gel plates and elutedwith CH₂Cl₂:hexane 1:1 to afford AS4 (R³=Ph, R⁴=p-ClPh).

Method AS, Step 4:

AS4 (R³=Ph, R⁴=p-ClPh) (0.12 g) and methylguanidine, HCl (AS6, R¹=Me)(0.055 g) were mixed in absolute EtOH (5 ml) with triethylamine (0.2 ml)and then heated under reflux for 20 h. The resulting mixture wasconcentrated and then partitioned between CH₂Cl₂ and H₂O. The driedCH₂Cl₂ was concentrated in vacuo to give a residue which was placed onpreparative silica gel plates and eluted with CH₂Cl₂:MeOH 9:1 to affordAS5 (R³=Ph, R⁴=p-ClPh and R¹=Me).

The following compounds were synthesized using similar methods: Obs.Obs. # Structure MW m/e # Structure MW m/e 419

299 300 411

265 266 420

309 310 412

265 266 421

325 326 413

271 272 422

343 344 414

271 272 423

343 344 415

279 280 424

421 422 416

295 296 425

482 483 417

295 296 426

512 513 418

299 300 427

560 561

Method AT, Step 1:

AT1, prepared using a method similar to Method H, Step 1, 2 and 3, (n=4,R³=R⁴=n-Bu) (0.146 g) in MeOH (3 ml) and 1N NaOH (0.727 ml) were stirredovernight at rt. The mixture was concentrated and then partitioned inwater (pH ˜3, adjusted using conc. HCl) and EtOAc. The dried EtOAc layerwas concentrated in vacuo to afford AT2 (n=4, R³=R⁴=n-Bu).

Method AT, Step 2:

Compound AT2 (n=4, R³=R⁴=n-Bu) (0.012 g). in MeCN (1 ml) was treatedwith EDC resin (0.12 g, 1.44 mmol/g), HOBT (0.004 g) in THF (1 ml), andn-butylamine (R¹⁵=H, R¹⁶=n-butyl) (0.007 ml). The reaction was carriedout overnight at rt. before Argonaut PS-NCO resin (0.150 g),PS-polyamine resin (0.120 g) and THF (2 ml) were added and the mixtureshaken for 4 h. The reaction mixture was filtered and resin washed withTHF (2 ml). The combined organic phase was concentrated in vacuo beforethe residue was treated with 1N HCl in MeOH (1 ml) for 4 h followed byevaporation of solvent to give AT3 (n=4, R³=R⁴=n-Bu, R¹⁵=H andR¹⁶=n-Butyl).

The following compounds were synthesized using similar method: Obs. #Structure MW m/e 428

324 325 429

325 326 430

338 339 431

339 340 432

366 367 433

368 369 434

380 381 435

382 383 436

400 401 437

406 407 438

414 415 439

414 415 440

420 421 441

428 429 442

444 445 443

458 459

A published procedure was adapted (Varga, I.; Nagy, T.; Kovesdi, I.;Benet-Buchholz, J.; Dormab, G.; Urge, L.; Darvas, F. Tetrahedron, 2003,(59) 655-662).

AU1 (R¹⁵=H, R¹⁶=H) (0.300 g), prepared according to procedure describedby Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R.,(Vogel's Textbook of Practical Organic Chemistry. 5^(th) ed. Longman:new York, 1989; pp 1034-1035), AU2 (HCl salt, R¹=Me) (0.237 g), 50% KOH(0.305 ml), 30% H₂O₂ (0.115 ml) and EtOH (4.6 ml) were heated in asealed tube for 2 h. Reaction mixture was concentrated and extractedwith CH₂Cl₂. The dried organic solution was concentrated in vacuo togive a residue which was placed on preparative silica gel plates elutingwith CH₂Cl₂:MeOH 9:1 to afford AU3 (R¹⁵=H, R¹⁶=H, R¹=Me).

The following compounds were synthesized using similar method: Obs. #Structure MW m/e 444

265 266 446

280 281 447

285 286 448

285 286 449

309 310 450

309 310

Method AV, Step 1:

In a microwave tube, AV1 (R³=Me, R⁴=Bu-i) (0.0012 g) and AV2 (R²²=OPh)(0.0059 ml) in isopropanol (2 ml) was placed in a microwave at 125° C.for 5 min. The reaction mixture was concentrated in vacuo to give AV3(R³=Me, R⁴=i-Bu, R²²=OPh).

Method AV, Step 2:

AV3 (R³=Me, R⁴=i-Bu, R²²=OPh) in CH₂Cl₂ (1 ml) and TFA (1 ml) was shakenfor 2 h and the concentrated in vacuo and purified on Prep LCMS toafford AV4 (R³=Me, R⁴=i-Bu, R²²=OPh).

The following compounds were synthesized in a simlar fashion. Obs. #Structure MW m/e 451

378 379 452

396 397 453

416 417

Method similar to Method U was used for this transformation. Thefollowing compounds were generated using similar methods.

The following compounds were synthesized in a similar fashion: Obs. #Structure MW m/e 454

341 342 455

341 342 456

342 343 457

342 343 458

347 348 459

359 360 460

323 324 461

294 295

Method AX, Step 1.

A literature procedure was adapted. (J-Q Yu and E. J. Corey, OrganicLetters, 2002, 4, 2727-2730).

To a 400 ml DCM solution of AX1 (n=1, R⁴=phenethyl) (52 grams) in a icebath was added 5 g of Pd/C (5% w/w), 50 g of potassium carbonate and 100ml of anhydrous t-BuOOH. The mixture was stirred in air for overnightbefore it was diluted with DCM and washed with water. The residue afterremoval of organic solvent and drying was chromatographed usingethylacetate/hexane to give 25 g of AX2 (n=1, R⁴=phenethyl).

Method AX, Step 2.

A solution of AX2 (4.5 g, n=1, R⁴=phenethyl) in MeOH (50 ml) was treatedwith 0.4 g of Sodium borohydride and the reaction was stirred for 30 minbefore the solvent was removed and residue chromatographed to give amixtrue of AX3 (n=1, R⁴=phenethyl) and AX4 (n=1, R⁴=phenethyl) which wasseparated using an AS chiralpak column eluted with 8% IPA in Hexane(0.05% DEA) to give 2.1 g of AX3 (n=1, R⁴=phenethyl) as the firstfraction and 2.2 g of AX4 (n=1, R⁴=phenethyl) as the second fraction.

Method AX, Step 3.

A 100 ml methanolic solution of AX4 (n=1, R⁴=phenethyl) (2.2 g) and1,1′-bis(di-1-propylphosphino)ferrocene (1,5-cyclooctadiene)rhodium (I)tetrafluoroborate (0.4 g, 0.57 mmol) was hydrogenated at 55 psiovernight. The reaction was concentrated, and the brown oil was purifiedby silica gel chromatography to yield AX6 (n=1, R⁴=phenethyl) (1.79).

The following compounds were generated using similar method.

A solution of AY1 (n=1; 1.5 g, 3.4 mmol), 5% Rh/C (1.5 g), 5% Pd/C (0.5g) in AcOH (30 mL) was shaken in a Parr apparatus at 55 psi for 18hours. The vessel was flushed with N₂, and the reaction was filteredthrough a pad of celite. After concentration AY2 was obtained which wascarried on without purification. MS m/e: 312.0 (M⁺H).

AY3 was generated using similar method.

Method AZ, Step 1

To a solution of AZ1 (n=1, R¹=Me, R³=2-cyclohexylethyl) (0.441 g, 1.01mmol), generated from AY2 using Method C and Method H Step 3, in DCM wasadded Dess-Martin Periodinane (0.880 g, 2.07 mmol). The reaction wasstirred for 3 hours at room temperature. The reaction was quenched withH₂O and diluted with EtOAc. After removal of the organic phase, theaqueous layer was extracted with EtOAc (3×). The combined organics weredried (Na₂SO₄), filtered, and concentrated. The residue was purified bysilica gel chromatography (0-100% EtOAc/hexanes) to yield AZ2 (n=1,R¹=Me, R³=2-cyclohexylethyl) (0.408 g, 0.94 mmol, 93% yield). MS m/e:434.1 (M⁺H).

Method AZ Step 2:

To a solution of AZ2 (n=1, R¹=Me, R³=2-cyclohexylethyl) (0.011 g, 0.025mmol) and AZ5 (R¹⁵=H and R¹⁶=m-pyridylmethyl) (0.0067 mL, 0.066 mmol) inDCE (1.8 mL) and MeOH (0.2 mL) was added AcOH (4 drops) andMP-cycanoborohydride resin (0.095 g, 2.42 mmol/g). The reaction wasagitated for 40 hours at room temperature. The reaction was treated with7N NH₃/MeOH, and solution was filtered. After concentration, the residuewas purified by silica gel HPLC (0-4% [(5% 7N NH₃/MeOH)/MeOH]/(50%DCM/hexanes) to furnish fraction 1 and fraction 2 which, after removalof solvent, were treated with 20% TFA in DCM for 3 h at r.t. to give AZ4(n=1, R¹=Me, R³=2-cyclohexylethyl, R¹⁵=H and R¹⁶=m-pyridylmethyl) (0.005g, 0.009 mmol) and the AZ3 (n=1, R¹=Me, R³=2-cyclohexylethyl, R¹⁵=H andR¹⁶=m-pyridylmethyl) (0.012 g, 0.022 mmol) respectively.

The following compounds were generated using similar methods: Obs. #Structure MW m/e 462

333 334 463

348 349 464

374 375 465

374 375 466

374 375 467

374 375 468

376 377 469

376 377 470

376 377 471

376 377 472

377 378 473

377 378 474

378 379 475

378 379 476

388 389 477

388 389 478

388 389 479

388 389 480

388 389 481

388 389 482

388 389 483

388 389 484

390 391 485

390 391 486

390 391 487

390 391 488

391 392 489

391 392 490

391 392 491

391 392 492

392 393 493

392 393 494

392 393 495

392 393 496

402 403 497

402 403 498

402 403 499

405 406 500

406 407 501

406 407 502

406 407 503

406 407 504

406 407 505

410 411 506

410 411 507

410 411 508

411 412 509

411 412 510

411 412 511

416 417 512

416 417 513

416 417 514

416 417 515

417 418 516

417 418 517

424 425 518

424 425 519

424 425 520

424 425 521

425 426 522

425 427 523

425 426 524

425 426 525

425 426 526

425 426 527

425 426 528

425 426 529

425 426 530

425 426 531

425 426 532

425 426 533

428 429 534

428 429 535

439 440 536

439 440 537

442 443 538

442 443 539

442 443 540

442 443 541

444 445 542

445 446 543

459 460 544

459 460

Method BA, Step 1:

BA1, prepared according to a literature procedure (Terao, Y; Kotaki, H;Imai, N and Achiwa K. Chemical and Pharmaceutical Bulletin, 33 (7),1985, 2762-2766) was converted to BA2 using a procedure described byColdham, I; Crapnell, K. M; Fernandez, J-C; Moseley J. D. and Rabot, R.(Journal of Organic Chemistry, 67 (17), 2002, 6185-6187).

¹H NMR(CDCl₃) for BA2: 1.42 (s, 9H), 4.06 (d, 4H), 4.09 (s, 1H), 4.18(s, 2H), 5.62 (d, 1H).

Method BA, Step 2:

BA3 was generated from BA2 using a literature procedure described byWinkler J. D.; Axten J.; Hammach A. H.; Kwak, Y-S; Lengweiler, U.;Lucero, M. J.; Houk, K. N. (Tetrahedron, 54 1998, 7045-7056). Analyticaldata for compound BA3: MS m/e: 262.1, 264.1 (M⁺H). ¹H NMR(CDCl₃) 1.43(s, 9H), 3.98 (s, 2H), 4.11 (d, 4H), 5.78 (d, 1H).

Method BB, Step 1;

Compound BB1 (n=1, R¹=Me, R³=cyclohexylethyl) was converted to BB2 (n=1,R¹=Me, R³=cyclohexylethyl) and BB3 (n=1, R¹=Me, R³=cyclohexylethyl)which were separated via a silica gel column eluted with EtOAc in Hexane(0-15%).

Method BB, Step 2;

Compound BB4 (n=1, R¹=Me, R³=cyclohexylethyl) was generated from BB2(n=1, R¹=Me, R³=cyclohexylethyl) using 20% TFA in DCM.

The following compounds were generated using similar method:

Method BC, Step 1;

Compound BC2 (n=1, R¹=Me, R³=cyclohexylethyl and R¹⁵=m-Pyridyl) wasobtained from BC1 (n=1, R²=Me, R³=cyclohexylethyl) using method L step2.

Method BC, Step 2;

Compound BC3 (n=1, R¹=Me, R³=cyclohexylethyl and R¹⁵=m-Pyridyl) wasobtained from BC2(n=1, R¹=Me, R³=cyclohexylethyl and R⁵=m-Pyridyl) usingmethod L step 3.

The following compounds were generated using a similar method: Obs. #Structure MW m/e 552

374 375 553

388 389 554

388 389 555

388 389 556

388 389 557

390 391 558

390 391 559

402 403 560

402 403 561

402 403 562

402 403 563

404 405 564

404 405 565

404 405 566

404 405 567

410 411 568

410 411 569

411 412 570

411 412 571

411 412 572

411 412 573

411 412 574

411 412 575

416 417 576

416 417 577

416 417 578

416 417 579

424 425 580

424 425 581

424 425 582

424 425 583

425 426 584

425 426 585

425 426 586

425 426 587

425 426 588

425 426 589

425 426 590

430 431 591

430 431 592

438 439 593

438 439 594

439 410

Method BD, Step 1;

Compound BD2 (n=1, R¹=Me, R³=cyclohexylethyl and R¹⁵=Ph) was obtainedfrom BD1 (n=1, R²=Me, R³=cyclohexylethyl) using Method N, Step 1.

Method BD, Step 2;

Compound BD3 (n=1, R¹=Me, R³=cyclohexylethyl and R¹⁵=Ph) was obtainedfrom BD2 (n=1, R¹=Me, R³=cyclohexylethyl and R¹⁵=m-Pyridyl) using MethodN, Step 2.

The following compounds were generated using a similar method: Obs. #Structure MW m/e 595

440 441 596

460 461

Method similar to Method M was adapted for these transformations. Thefollowing compounds were generated similar methods. Obs. # Structure MWm/e 597

405 406 598

439 440

Method BF, Step 1:

Method similar to Method T, Step 1 was used for the synthesis of BF2(n=1, R¹=Me and R³=phenethyl, R¹⁵=H and R¹⁶=n-propyl).

Method BF, Step 2:

Method similar to method L Step 3 was adapted for this transformation.

The following compounds were generated using similar methods. Obs. #Structure MW m/e 599

376 377 600

390 391 601

390 391 602

390 391 603

397 398 604

397 398 605

397 398 606

397 398 607

411 412

Method BG:

To a solution of BG1 (n=1, R³=cyclohexylethyl) (0.136 g, 0.31 mmol) inCH₂Cl₂ was added 2,6-lutidine, AgOTf, and butyl iodide. The reaction wasstirred at room temperature for 96 hours. The reaction was filteredthrough a pad of Celite, and the solution was concentrated. The residuewas purified by silica chromatography (0-100% EtOAc/hexanes) to furnishBG2 (n=1, R³=cyclohexylethyl, R¹⁵=n-butyl) (0.124 g, 0.25 mmol, 80%yield). MS m/e: 426.1 (M-OBu).

The following compound was prepared using similar method:

Method BH, Step 1.

Compound BH1 (n=1, R³=cyclohexylethyl and R¹⁵=n-butyl). (0.060 g, 0.12mmol) and 5% Pd(OH)₂/C (0.040 g) in EtOAc (1 mL)/MeOH (0.2 mL) wasstirred under an atmosphere of H₂ for 20 hours at room temperature. Thereaction was filtered through a pad of Celite, and the solution wasconcentrated. The crude product mixture BH2 (n=1, R³=cyclohexylethyl andR¹⁵=n-butyl) was carried on to the next step without purification.

Method BH, Step 2.

A solution of BH2 (n=1, R³=cyclohexylethyl and R¹⁵=n-butyl) wasconverted to a product mixture of BH4 and BH3 using a method similar toMethod C Step 1. The mixture was purified by silica gel chromatographyusing EtOAc/hexanes to yield BH4 (n=1, R²=Me, R³=cyclohexylethyl andR¹⁵=n-butyl) (0.032 g, 0.078 mmol, 56% yield) and BH3 (n=1, R²=Me,R³=cyclohexylethyl and R¹⁵=n-butyl) (0.008 g, 0.020 mmol, 14% yield).For BH4 (n=1, R²=Me, R³=cyclohexylethyl and R¹⁵=n-butyl), MS m/e:409.1M+H). For BH3 (n=1, R²=Me, R³=cyclohexylethyl and R¹⁵=n-butyl), MSm/e: 409.1 (M⁺H).

Method BH, Step 3.

Compound BH4 (n=1, R²=Me, R³=cyclohexylethyl and R¹⁵=n-butyl) (0.032 g,0.078 mmol) was converted to BH5 (n=1, R²=Me, R³=cyclohexylethyl andR¹⁵=n-butyl) (0.016 g, 0.043 mmol, 57% yield) using a method similar toMethod A, step 3. MS m/e: 392.1 (M⁺H).

The following compound was generated using a similar method: Obs. #Structure MW m/e 608

391 392 609

391 392 610

391 392

A solution of BI1 (0.020 g, 0.040 mmol) in DCM (1 mL) was degassed usingfreeze/pump/thaw (4×) method. At the end of the fourth cycle Crabtree'scatalyst was added and the system was evacuated. While thawing, thesystem was charged with hydrogen gas, and the reaction was stirred atroom temperature for 16 hours under an H₂ atmosphere. The reaction wasconcentrated, and the brown oil was purified by reverse phase HPLC tofurnish BI2 (0.011 g, 0.022 mmol, 55% yield). MS m/e: 368.2 (M⁺H).

Method BJ, Step 1

A mixture of 2 ml dioxane solution of BJ1 (R¹=Me, R³=Me) (140 mg, 0.5mmol) generated using Method BK Steps 1 & 2, indole (1.2 eq), potassiumt-Butoxide (1.4 eq), Pd₂(dba)₃ (0.02 eq) and2-di-t-butylphospinobiphenyl (0.04 eq) in a sealed tube was irradiatedin a microwave oven at 120° C. for 10 min and the mixture was separatedvia a silica gel column to give BJ2 (R¹=Me, R³=Me) (0.73 mg).

Method BJ, Step 2

BJ2 (R¹=Me, R³=Me) was converted to BJ3 (R¹=Me, R³=Me) using Method BK,Steps 3 & 4. Obs. Mass for BJ3 (R¹=Me, R³=Me): 319.2. Obs. # StructureMW m/e 614

318 319

Method BK, Step 1:

Hydantoin BK2 (R³=N-benzyl-3-piperidyl, R⁴=n-Bu) was prepared, accordingto Method D, Step 1 from the corresponding ketone BK1(R³=N-benzyl-3-piperidyl, R⁴=n-Bu). Analytical data for BK2(R³=N-benzyl-3-piperidyl, R⁴=n-Bu): (M⁺H)=330.1.

Method BK, Step 2:

To a suspension of hydantoin BK2 (R³=N-benzyl-3-piperidyl, R⁴=n-Bu) (138mg, 0.419 mmol) in DMF (1.5 ml) was added dimethylformamidedimethylacetal (0.11 ml, 0.84 mmol). The resulting mixture was heated ina 100° C. oil bath for 16 h and then cooled to RT and concentrated undervacuum. This crude residue was purified by column chromatography(MeOH/DCM) to give product BK3 (R³=N-benzyl-3-piperidyl, R⁴=n-Bu) (140mg, 0.408 mmol, 97%), (M⁺H)=344.1.

Method BK, Step 3:

To a solution of a portion of BK3 (R³=N-benzyl-3-piperidyl, R⁴=n-Bu) (70mg, 0.20 mmol) in toluene (1 ml) was added Lawesson's reagent (107 mg,0.26 mmol). The resulting mixture was placed in an oil bath at 60° C.for 16 h and then at 100° C. for 24 h. After cooling to RT, the reactionwas quenched by addition of several drops of 1 N HCl and then dilutedwith EtOAc and 1 N KOH. The phases were separated and the aqueous layerextracted with EtOAc (2×). The organic portions were combined, washedwith brine, dried over MgSO₄, filtered, and concentrated. This cruderesidue was purified by preparative TLC (1000 μm silica, 15% EtOAc/DCM)to give two separated diastereomers BK4 (R³=N-benzyl-3-piperidyl,R⁴=n-Bu) (24 mg, 0.067 mmol, 33%, MS: (M⁺H)=360.2) and BK5(R³=N-benzyl-m-piperidyl, R⁴=n-Bu) (22 mg, 0.062 mmol, 31%, MS:(M⁺H)=360.2).

Method BK, Step 4:

Diastereomer BK5 (R³=N-benzyl-3-piperidyl, R⁴=n-Bu) was treated withNH₄OH (2 ml) and t-butyl hydrogen peroxide (70% aqueous, 2 ml) in MeOH(4 ml) for 24 h. After concentration, the crude sample was purified bypreparative TLC (1000 mm silica, 7.5% 7N NH₃/MeOH in DCM). The resultingsample was dissolved in DCM (1 ml), treated with 4N HCl in dioxane for 5min, and finally concentrated to give diastereomeric products BK7(R³=N-benzyl-3-piperidyl, R⁴=n-Bu) (12 mg, 0.029 mmol, 43%). ¹H NMR(CD₃OD) δ 7.60 (m, 2H), 7.49 (m, 3H), 4.39 (ABq, J_(AB)=12.8 Hz,Δν_(AB)=42.1 Hz, 2H), 3.69 (m, 1H), 3.39 (br d, J=13.6 Hz, 1H), 3.20 (s,3H), 2.96 (m, 2H), 2.45 (m, 1H), 1.99 (m, 1H), 1.92-1.78 (m, 3H), 1.68(br d, J=12.4 Hz, 1H), 1.50 (dq, J_(d)=3.6 Hz, J_(q)=12.8 Hz, 1H),1.36-1.22 (m, 4H), 1.03 (m, 1H), 0.90 (t, J=7.2 Hz, 3H). LCMS: t_(R)(doubly protonated)=0.52 min, (singly protonated)=2.79 min; (M⁺H) forboth peaks=343.2.

The following compounds were synthesized using similar methods: Obs. #Structure MW m/e 615

281 282

To a 2 ml Methanolic solution of BL1 (n=1, R³=cyclohexylethyl, R¹=Me)(10 mg) was added BL3 (HCl salt, R¹⁵=H, 2 eq) and NaOAc (2 eq) and themixture was heated to 60 C for 16 h. After removal of solvent, theresidue was treated with 20% TFA in DCM for 30 min before the solventwas evaporated and residue purified using a reverse phase HPLC to giveBL2 (n=1, R³=cyclohexylethyl, R¹=Me and R¹⁵=H).

The following compounds were synthesized using similar methods. Obs. #Structure MW m/e 616

348 349 617

388 389

Method BM, Step 1:

To a toulene solution (3 ml) of BM1 (n=1, R³=cyclohexylethyl, R²=Me)(0.050 mg) was added 1.5 eq of diphenylphosphorylazide and 1.5 eq of DBUand the solution was stirred at r.t. overnight. The reaction mixture wasdiluted with EtOAc and washed with 1% aq HOAC before the organic layerwas dried and solvent evaporated. The residue was chromatographed usingEtOAc/Hex to give a product that was treated with triphenylphosphine (2eq) in THF (1% water) overnight to give BM2 (n=1, R³=cyclohexylethyl,R²=Me) after reverse phase purification.

Method BM Step 2:

To a DCM solution of BM2 (n=1, R³=cyclohexylethyl, R²=Me) was added 1 eqof benzyloxycarbonyl-OSu and the reaction was stirred overnight beforethe solvent was evaporated and residue chromatographed to give BM3 (n=1,R³=cyclohexylethyl, R²=Me).

Compound BM4 (n=1, R³=cyclohexylethyl, R²=Me) and BM5 (n=1,R³=cyclohexylethyl, R²=Me) were generated from BM2 (n=1,R³=cyclohexylethyl, R²=Me) and BM3 (n=1, R³=cyclohexylethyl, R³=Me)through Boc-deprotection.

The following compounds were synthesized using similar method: Obs. #Structure MW m/e 618

332 333 619

468 469

A mixture of Pd(OAc)₂ (9 mg), triethylamine (17 microliter),triethylsilane (11 microliter) and BN1 (20 mg) in DCM was hydrogenatedat 1 atm at rt for 1.5 h before the reaction was filtered through aCelite pad to give BN2 after removal of solvent.

Method BO

The following compounds were generated through boc-deprotection of thecorresponding starting material using 50% TFA in DCM, rt 30 min. Obs. #Structure MW m/e 620

266 267 621

266 267 622

274 275 623

274 275 624

288 289 625

320 321 626

320 321

Method BP, Step 1

To a solution of BP1 (n=1, R¹=Me, R²=H, R³=cyclohexylethyl) (0.012 g,0.028 mmol) in CH₂Cl₂ (0.5 mL) was added 2,6-lutidine (0.010 mL, 0.086mmol), AgOTf (0.024 g, 0.093 mmol), and benzyl bromide (0.010 mL, 0.084mmol). The reaction was stirred at room temperature for 16 hours. Thesolid was filtered, and after concentration the residue was purified byreverse phase HPLC to yield BP2 (n=1, R¹=Me, R²=H, R³=cyclohexylethyl)(0.010 g, 0.019 mmol). MS m/e: 526.1 (M⁺H).

Method BP, Step 2

BP3 (n=1, R¹=Me, R²=H, R³=cyclohexylethyl) was prepared from BP2 (n=1,R¹=Me, R²=H, R³=cyclohexylethyl) using 30% TFA/DCM. MS m/e: 426.1 (M⁺H).Obs. # Structure MW m/e 627

425 426

Method BQ Step 1:

BQ1 was prepared according to Method AZ.

To a solution of BQ1 (n=1, R¹=Me, R²=H, R³=cyclohexylethyl) (0.004 g,0.007 mmol) in CH₂Cl₂ (0.3 mL) was added DIEA (0.007 mL, 0.040 mmol),acetic acid (0.001 mL, 0.017 mmol), HOBt (0.003 g, 0.019 mmol), and EDCI(0.003 g, 0.016 mmol). The reaction was stirred at room temperature for16 hours. The reaction was concentrated and purified by reverse phaseHPLC to provide BQ2 (n=1, R¹=Me, R²=H, R³=cyclohexylethyl) (0.003 g,0.005 mmol). MS m/e: 627.1 (M⁺H).

Method BQ Step 2:

BQ2 (n=1, R¹=Me, R²=H, R³=cyclohexylethyl) (0.003 g, 0.005 mmol) wastreated with 20% TFA/CH₂Cl₂ (1 mL) in the presence of PS-thiophenolresin (0.030 g, 1.42 mmol/g) for 3 hours. The solution was filtered andconcentrated to produce B03 (n=1, R¹=Me, R²=H, R³=cyclohexylethyl)(0.002 g, 0.005 mmol). MS m/e: 377.2 (M⁺H). # Structure MW Obs. m/e 628

376 377

Method BR, Step 1:

To a solution of BR1 (n=1, R¹=Me, R²=H, R³=cyclohexylethyl) (0.004 g,0.007 mmol) in pyridine (0.2 ml) was added DMAP (a few crystals) andmethylsulfonyl chloride (3 drops). The reaction was stirred at roomtemperature for 6 days. The reaction was quenched with water and dilutedwith CH₂Cl₂. The organic layer was removed, and the aqueous phase wasextracted with CH₂Cl₂ (3×). After concentration, the brown residue waspurified by reverse phase HPLC to yield BR2 (n=1, R¹=Me, R²=H,R³=cyclohexylethyl) (0.003 g, 0.004 mmol). MS m/e: 663.2 (M⁺H).

Method BR, Step 2:

BR3 (n=1, R¹=Me, R²=H, R³=cyclohexylethyl) was prepared from BR2 (n=1,R¹=Me, R²=H, R³=cyclohexylethyl) following a procedure similar to MethodBQ Step 2. MS m/e: 413.1 (M⁺H). # Structure MW Obs. m/e 629

412 413

Method BS Step 1:

To a solution of BS1 (n=1, R¹=Me, R²=H, R³=cyclohexylethyl) (0.003 g,0.006 mmol) in CH₂Cl₂ (0.3 mL) was added phenyl isocyanate (2 drops).The reaction was stirred at room temperature for 16 hours. The reactionwas concentrated and purified by reverse phase HPLC to provide BS2 (n=1,R¹=Me, R²=H, R³=cyclohexylethyl) (0.002 g, 0.002 mmol). MS m/e: 823.5(M⁺H).

Method BS Step 2:

Compound BS2 (n=1, R¹=Me, R¹²=H, R³=cyclohexylethyl) was subjected tothe same conditions in Method BQ Step 2. The crude mixture preparedabove was treated with LiOH (0.006 g, 0.25 mmol) in MeOH (0.3 mL) for 2hours. The reaction was concentrated, and the residue was purified byreverse phase HPLC to furnish BS3 (n=1, R¹=Me, R²=H, R³=cyclohexylethyl)(0.0012 g, 0.002 mmol). MS m/e: 454.1 (M⁺H). Obs. # Structure MW m/e 630

453 454

Method BT:

To a round bottom flask were added compound BT1 (R¹=Me, R³=Me) (100 mg,0.29 mmol), anhydrous toluene (2 ml), 3-aminopyridine (55 mg, 0.58 mmol)and 2-(di-tert-butyl phosphino) biphenyl (17 mg, 0.058). The solutionwas then degassed by N₂ for 2 minutes before NaO-t-Bu (61 mg, 0.638mmol) and Pd₂(dba)₃ (27 mg, 0.029 mmol) were added. The reaction wasstirred at 80° C. for 22 hours. After cooling down to room temperature,the reaction was poured to cold water and extracted by CH₂Cl₂. Thecombined organic layer was then dried over Na₂SO₄. After the filtration,the concentrated residue was separated by TLC (CH₃OH:CH₂Cl₂=1:10) andreverse phase HPLC (10%-100% acetonitrile in water w/0.1% formic acid)to produce the desired compound BT2 (R¹=Me, R³=Me and R²¹=m-pyridyl) asa formate salt (23.6 mg, white solid, 20%). ¹HNMR (CDCl₃) δ 7.50-6.90(m, 13H), 3.14 (s, 3H) MS m/e 358 (M⁺H). Obs. # Structure MW m/e 631

347 348 632

356 357 633

357 358 634

357 358 635

357 358 636

358 359

Method BU, Step 1,

To a round bottmed flask containing BU1 (m=1, n=1, R¹=Me,R³=Cyclohexylethyl) (99 mg, 0.307 mmol) of the trifluroacetic acid saltof pyrollidine derivative in 5 ml of DCM was added (86 μL, 0.614 mmol)of triethylamine followed by addition of (76 mg, 0.307 mmol)N-(benzyyloxycarbonyloxy)succinimide. Stir at room temperature for 18 h.Dilute the mixture with DCM and extract with sat'd NaHCO₃ soln, thenwater. Collect the organic portion and dry over Na₂SO₄, filter andconcentrate in vacuo. Purify by silica gel chromatography (eluting with0 to 60% EtOAc/hexanes) to yield BU2 (m=1, n=1, R¹=Me,R³=Cyclohexylethyl) (130 mg, 0.284 mmol, 93% yield). MS m/e: 458.1(M⁺H).

Method BU, Step 2,

To a solution of BU2 (m=1, n=1, R¹=Me, R³=Cyclohexylethyl) (130 mg) in 1ml of MeOH in a reaction vial was added 0.5 ml of a solution of 70%tBuOOH in water and 0.5 ml of NH₄OH. Seal the vial and shake at roomtemperature for 72 h. The mixture was concentrated in vacuo. The mixturewas diluted with 1 ml of MeOH and a mixture 30 mg of NaHCO₃ and Boc₂O(87 mg, 0.398 mmol) were added. The solution mixture was stirred at roomtemperature for 18 h before it was concentrated and the residue purifiedby silica gel chromatography using EtOAc/hexanes to yield the BU3 (m=1,n=1, R¹=Me, R³=Cyclohexylethyl) (90 mg, 0.167 mmol, 58% yield). MS m/e:541.1, 441.1 (M⁺H).

Method BU, Step 3,

A solution of BU3 (m=1, n=1, R¹=Me, R³=Cyclohexylethyl) (90 mg, 0.167mmol) in 5 ml of MeOH was hydrogenated using 100 mg of Pd(OH)₂—C (20%w/w) at 1 atm for 1 h. The reaction mixture was filtered through a padof diatomaceous earth and the pad was washed with MeOH. Concentration ofthe collected organic portions in vacuo yielded BU4 (m=1, n=1, R¹=Me,R³=Cyclohexylethyl) (47 mg 0.116 mmol, 70% yield). MS m/e: 407.1 (M⁺H).

Method BU, Step 4,

To a vial containing 10 mg of powdered 4 4′ molecular sieves was added3-methoxyphenyl boronic acid (60 mg, 0.395 mmol) then 3 ml of anhydrousMeOH. To this mixture was added pyridine (100 ml, 0.650 mmol), Cu(OAc)₂(7 mg, 0.038 mmol), and BU4 (m=1, n=1, R¹=Me, R³=Cyclohexylethyl) (7.83mg, 0.019 mmol) and the mixture was stirred at room temperature for 96 hbefore it was quenched with 0.25 ml of 7N ammonia in methanol solution.The reaction mixture was extracted with water and DCM and the organiclayers were dried and concentrate in vacuo. The residue was purified viaa reverse-phase HPLC to give a product which was treated with 5 ml of40% of TFA in DCM for 5 h. After removal of the volatiles, the residuewas purified using a reverse phase HPLC system to furnish BU5 (m=1, n=1,R¹=Me, R³=Cyclohexylethyl and R²=m-MeOPh) as the formic acid salt (0.7mg, 0.0015 mmol, 30.1% yield). MS m/e: 413.1 (M⁺H). Obs. # Structure MWm/e 637

358 359 638

412 413

Method BV Step 1:

The method was adapted from a literature procedure (Page et al.,Tetrahedron 1992, 35, 7265-7274)

A hexane solution of nBuLi (4.4 mL, 11 mmol) was added to a −78 Csolution of BV2 (R⁴=phenyl) (2.0 g, 10 mmol) in THF (47 mL). After 60minutes at −78 C, a solution of BV1 (R³=3-bromo-4-fluorophenyl) (2.24 g,11 mmol) was added and the reaction slowly warmed to RT over 18 h. Thereaction mixture was quenched with saturated ammonium chloride solutionand extracted with CH₂Cl₂ (2×), dried over MgSO4 and concentrated undervacuum. The resulting oil was subjected to silica gel chromatographyusing 4-10% EtOAc/Hexanes to give a white solid BV3:(R³=3-bromo-4-fluorophenyl and R⁴=phenyl) (1.69 g, 4.23 mmol, 42%). ¹HNMR (CDCl₃) δ 7.61 (m, 2H), 7.27 (m, 3H), 6.94 (m, 1H), 6.92 (m, 1H),6.68 (m, 1H), 3.15 (bs, 1H), 2.57-2.73 (m, 4H), 1.89 (m, 2H).

Method BV Step 2:

A solution of BV3 (R³=3-bromo-4-fluorophenyl and R⁴=phenyl) (1.69 g,4.23 mmol) in acetone (40 mL) was slowly added via addition funnel to a0° C. solution of N-bromosuccinimide (NBS, 11.3 g, 63.3 mmol) in acetone(200 mL) and water (7.5 mL). The mixture was slowly warmed to RT, andquenched after 60 minutes with 10% aqueous Na₂SO₃. After diluting withCH₂Cl₂, the layers were separated, and the organic layer washed withwater (2×), brine (1×) and dried over MgSO₄. Concentration under vacuumafforded an oil which was subjected to silica gel chromatography using5% EtOAc/Hexanes to give a solid BV4 (R³=3-bromo-4-fluorophenyl andR⁴-phenyl) (690 mg, 2.24 mmol, 53%). ¹H NMR (CDCl₃) δ 8.19 (m, 1H), 7.93(m, 3H), 7.66 (m, 1H), 7.50 (m, 2H), 7.20 (m, 1H).

Method BV Step 3:

BV5 (R³=3-bromo-4-fluorophenyl and R⁴=phenyl and R¹=Me and R²=H) wasprepared from BV4 (R³=3-bromo-4-fluorophenyl and R⁴=phenyl) using MethodAS, Step 4. Obs. # Structure MW m/e 639

361 362 640

361 NA

To an oven-dried vial was added Pd₂(dba)₃ (15.4 mg, 0.0168 mmol) and2-(Di-t-butylphosphino)biphenyl (10.0 mg, 0.0336 mmol) followed byaddition of a solution of BW1 (R⁴=Me; R¹=Me and n=1) (56.8 mg, 0.168mmol) in 2 mL of anhydrous THF. 2-Bromopyridine (17.0 mL, 0.178 mmol)was added followed by addition of 0.80 mL of 1.0 N LHMDS solution inTHF. The reaction mixtures was stirred at 35° C. for 90 min followed byaddition of MeOH and filteration through a silica gel pad. Purificationby silica gel chromatography (0 to 100% EtOAc in hexanes) yielded theproduct which was treated with 5 mL of a 30% TFA in DCM solution to giveBW2 after concentration and purification via a reverse phase column(R⁴=Me; R¹=Me; R²⁼²-pyridyl and n=1) (69.3 mg, 99%). ES_LCMS (m/e):416.2

Method BX, Step 1

To a solution of BX1 (R⁴=Me and n=1) (0.78 g, 3.63 mmol) in 10 mL ofanhydrous DMF, was added N-Boc-N′-methyl thiourea (0.70 g, 3.70 mmol),EDCI.HCl (0.90 g, 4.71 mmol), and diisopropylethylamine (2.5 mL). Themixture was stirred at RT for 16 h before it was quenched with water andextracted with EtOAc (3×50 mL). The organic solution was dried,concentrated and the residue chromatographed via a silica gel column toyield BX2 (R¹=R⁴=Me and n=1) (1.23 g, 100%). ES_LCMS (m/e): 340.1

Method BX, Step 2

To a solution of BX2 (R¹=R⁴=Me and n=1) (1.23 g, 3.63 mmol) in 40 mL ofanhydrous THF was added triphenylphosphine (1.43 g, 5.44 mmol) and themixture was cooled to 0° C. followed by slow addition ofdiisopropylcarbodiimide (1.07 mL, 5.44 mmol). After the mixture wasstirred for 15 min at 0° C., nicotinoyl azide (Synthesis, 2004 (17),2886) (0.66 g, 4.71 mmol) was added in one portion and the reaction wasallowed to warm to RT and stir for 3 h. The reaction was diluted withEtOAc (200 mL) and washed with water (3×100 mL). The residue from theorganic layer was purified through a silica gel column to yield theproduct azide which was hydrogenation using 20% Pd(OH)₂/C (0.64 mg) inMeOH to give BX3 (R¹=R⁴=Me and n=1). ES_LCMS (m/e): 339.1.

Method BY

The following compounds were synthesized using methods similar toMethods AO or AP.

Method BZ

The following aminoacids were generated using methods similar to MethodD

Compound CA2 (R³=R⁴=Ph; Z=m-phenylene, R¹⁵=H and R¹⁶=cyclopentyl) wasobtained from CA1 (R³=R⁴=Ph; Z=m-phenylene, R¹⁵=H and R¹⁶=cyclopentyl)using a method similar to Method G.

Method CB

The following compounds were synthesized using methods similar to MethodE and/or AX.

Method CC, Step 1.

To a methanol solution (20 mL) of CC1 (5 g) cooled to 0° C. was addedsodium borohydride (1 eq) and the reaction was stirred for 30 min beforethe reaction mixture was evaporated to dryness then extracted withDCM/water. The DCM fractions were pooled, dried (MgSO₄), filtered andconcentrated to dryness. The crude product was dissolved in 20 mL. ofanhydrous DCM. To this solution was added t-butyldimethylchlorosilane (2eq.) and imidazole (2 eq.). The reaction was stirred overnight at RTbefore it was quenched DCM and saturated NaHCO₃. The organic phase wasdried (MgSO₄), filtered and evaporated to dryness to give crude productCC2.

Method CC, Step 2.

A literature procedure was adapted (Aust. J. Chem. 1990, 43(7), 1195).Compound CC2 (50 g) in 80 mL. THF was added to mercuric oxide (1.5 eq.)and borontrifluoride etherate (1.6 eq.) in 540 mL. of THF/H₂O (5:1) andthe mixture was stirred under nitrogen for 2 h before the reaction wasquenched with saturated NaHCO₃ (aq.) and ether. The ether phase wasdried over anhyd. Na₂SO₄, filtered through a silica pad and concentratedto give crude CC3.

Method CC, Step 3.

To CC3 (10.4 grams) in 200 mL MeOH was added 1.1 eq. of sodiumborohydride and the mixture was stirred for 30 min before the reactionmixture was concentrated and the residue partitioned in DCM/H₂O. Theorganic phase was dried over Na₂SO₄, filtered and concentrated. Theresidue was chromatographed to give product CC4.

Method CC, Step 4.

Compound CC4 (2.5) in 5 mL. anhydrous DCM was addedBis(1,2-diphenylphosphino)ethane (DPPE; 1.2 eq.) followed by carbontetrabromide (1.1 eq.) at 0° C. and the reaction was stirred for 30 min.The reaction was quenched with hexane and poured over a silica pad. Theorganic solution was evaporated to give product CC5 as an oil. ¹H-NMR(CDCl₃) δ 5.72, br s, 1H, 4.18, t, 1H, 3.83, q, 2H, 2.00-2.10, m, 2H,1.76-1.81, m, 2H, 1.43-1.56, m, 2H, 0.84, s, 9H, 0.03, s, 6H.

Method CC, Step 5.

Compound CC6 was generated from CC5 using a similar procedure in MethodE. Crude compound CC6 was purified by flash chromatography (gradient0-10% EtOAc in hexane). Two isomers were isolated during purificationisomer A which eluted first followed by isomer B.

ISOMER A: ¹H-NMR (CDCl₃) δ 7.26-7.37, m, 5H, 5.57, s, 1H, 5.38, s, 1H,5.02, q, 2H; 4.08, br s, 1H, 3.67, s, 3H, 3.08, d, 1H, 2.58, d, 1H,1.80-1.92, m, 1H, 1.60-1.75, m, 3H, 1.32-1.44, m, 3H, 0.83, s, 9H,0.35-0.45, m, 4H, 0.01, s, 6H.

ISOMER B: ¹H-NMR (CDCl₃) δ 7.286-7.36, m, 5H, 5.56, s, 1H, 5.39, s, 1H,5.06, q, 2H, 4.15, brs, 1H, 3.71, s, 3H, 3.06, d, 1H, 2.70, d, 1H,1.60-1.90, m, 4H, 1.33-1.48, m, 3H, 0.87, s, 9H, 0.37-0.51, m, 4H, 0.03,s, 6H. Yield 26% isomer A and 22% isomer B.

Method CC, Step 6.Compound CC7 was obtained from CC6 (isomer B) through treatment with 1 NTBAF in THF for 30 min followed by extraction with ether/water. Theorganic phase was separated and washed four times with water. Theaqueous phase was pooled and washed once with Et₂O (pH ˜6 to 7). Theorganic phase was dried over Na₂SO₄, filtered and evaporated to giveproduct CC7 in 94% yield. ¹H-NMR (CDCl₃) δ 7.28-7.39, m, 5H, 5.58, brs,1H, 5.49, brs, 1H, 5.10, d, 1H, 5.02, d, 1H, 4.09, brs, 1H; 3.72, s, 3H,3.14, d, 1H, 2.70, s, 1H, 1.79-1.87, m, 2H, 1.67-1.79, m, 1H, 1.53-1.67,m, 2H, 1.44-1.53, m, 2H.; 1.31-1.39, m, 1H, 0.35-0.54, m, 4H

Step 1: tert-Butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate

To a solution of tert-butyl2-(3-bromophenyl)-1-hydroxypropan-2-ylcarbamate (CD1; R⁴=Me) (1.5 g, 4.6mmol) in EtOAc (150 mL) at reflux was added IBX (3.82 g, 13.6 mmol, 3eq). Reflux was continued for another 2 h and then the mixture wascooled to RT. The white precipitate was filtered and the filtrate wasconcentrated. The residue was purified by chromatography on silica gelby eluting with EtOAc/hexanes to give 1.0 g (66%) of tert-butyl2-(3-bromophenyl)-1-oxopropan-2-yl carbamate (CD2; R⁴=Me) as a colorlessoil. ¹H NMR (CDCl₃) δ 9.42 (s, 1H), 7.69 (m, 1H), 7.60 (m, 1H),7.55-7.40 (m, 2H), 5.85 (bs, 1H), 1.96 (s, 3H), 1.56 (s, 9H).

Step 2: tert-Butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate

To a solution of tert-butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate(C D2; R⁴=Me) (1.0 g, 3 mmol) in dichloroethane (50 mL) was addedmethylamine (0.48 g, 6.1 mmol, 2 eq) in water (40%) and 1 mL of AcOH.The solution was allowed to stir at RT for 1 h followed by the additionof sodium triacetoxyborohydride (1.8 g, 8.5 mmol, 2.8 eq). The resultingmixture was stirred at RT for 16 h and quenched with MeOH. Afterstirring for 30 min the mixture was concentrated in vacuo. The residuewas purified by chromatography on silica gel by eluting with EtOAc/MeOHto give 0.62 g (60%) of tert-butyl2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate (CD3; R¹=Me,R⁴=Me) as a colorless oil. ¹H NMR (CDCl₃) δ 7.47(bs, 1H), 7.37 (m, 1H),7.27 (m, 1H), 7.23 (m, 1H), 5.97 (bs, 1H), 3.18-2.82 (m, 2H), 2.45 (s,3H), 1.74 (s, 3H), 1.40 (s, 9H). MS (ESI) m/e 342.9 (M⁺H)⁺.

Step 3: 4-(3-Bromophenyl)-1,4-dimethylimidazolidin-2-imine

tert-Butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate (CD3;R¹=Me, R⁴=Me) (0.62 g, 1.8 mmol) was dissolved in 25% TFA in DCM (25 mL)and the mixture was left stirring at RT for 1 h. The mixture wasconcentrated in vacuo and the residue was redissolved in CHCl₃ (20 mL).The solution was washed with 15% NaOH (10 mL) and the aqueous layer wasextracted with CHCl₃ (3×10 mL). The combined organic layer was driedover MgSO₄ and concentrated in vacuo to give 0.33 g (76%) of crude2-(3-bromophenyl)-N¹-methylpropan-1,2-diamine as a colorless oil. ¹H NMR(CDCl₃) δ 7.65(t, J=1.7 Hz, 1H), 7.41-7.34 (m, 2H), 7.21 (t, J=7.8 Hz,1H), 2.86 (dd, J=11.7, 0.6 Hz, 1H), 2.64 (dd, J=11.7, 0.6 Hz, 1H), 2.38(s, 3H), 1.54 (bs, 3H), 1.43 (s, 9H). MS (ESI) m/e 242.9 (M⁺H)⁺. Thecompound was used in the next step without further purification.

To a solution of 2-(3-bromophenyl)-N¹-methylpropan-1,2-diamine (0.12 g,0.50 mmol) in EtOH (10 mL) was added BrCN (0.073 g, 0.70 mmol, 1.4 eq).The mixture was stirred at RT for 16 h and then concentrated in vacuo.The residue was redissolved in CHCl₃ (20 mL) and the solution was washedwith 15% NaOH (10 mL). The aqueous layer was extracted with CHCl₃ (3×10mL) and the combined organic layer was dried (MgSO₄), and concentratedto give 0.14 g (100%) of4-(3-bromophenyl)-1,4-dimethylimidazolidin-2-imine (CD4; R¹=Me, R⁴=Me)as a colorless oil. ¹H NMR (CDCl₃) δ 7.42 (t, J=1.7 Hz, 1H), 7.35 (dd,J=8.1, 1.7 Hz, 2H), 7.15 (t, J=8.1 Hz, 1H), 3.62 (d, J=9.3 Hz, 1H), 3.53(d, J=9.0 Hz, 1H), 3.08 (s, 3H), 1.56 (bs, 3H). MS (ESI) m/e 268.1,270.1 (M⁺H)⁺.

Step 4:4-(3-(3,4-Difluorophenyl)phenyl)-1,4-dimethylimidazolidin-2-imine

A mixture of 4-(3-bromophenyl)-4-methyloxazolidin-2-imine (0.027 g, 0.1mmol, 1 eq), 3,4-difluorophenyl boronic acid (0.020 g, 0.13 mmol, 1.3eq), FibreCat (20 mg), anhydrous ethanol (2 mL), and a 1N K₂CO₃ aqueoussolution (0.12 mL, 0.12 mmol, 1.2 eq) was heated in a microwave reactor(Emrys Optimizer) at 110° C. for 15 min. The mixture was transferred toa prepacked column of Si-carbonate (2 g, 0.79 mmol/g), which had beenconditioned with MeOH/DCM (1:1). The column was eluted with 1:1 MeOH/DCM(3×3 mL) and the eluants were collected and concentrated to give 0.019 g(63%) of4-(3-(3,4-difluorophenyl)phenyl)-1,4-dimethylimidazolidin-2-imine (CD5;R¹=Me, R⁴=Me, R²¹=3,4-difluorophenyl) as a white solid. ¹H NMR (CDCl₃) δ7.60 (s, 1H), 7.50-7.20 (m, 6H), 3.48 (m, 2H), 2.79 (s, 3H), 1.66 (s,3H). MS (ESI) m/e 302.2 (M⁺H)⁺, HPLC (A) R_(t)=5.48 min.

Alternative for Method CD for compound: R¹=OR¹⁵

Alternative Method CD, Step 2: tert-Butyl2-(3-bromophenyl)-1-(methoxyamino)propan-2-ylcarbamate

To a solution of tert-butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate(CD2; R⁴=Me) (2.7 g, 8.2 mmol) in dichloroethane (40 mL) was addedmethoxylamine hydrochloride (0.89 g, 10.7 mmol, 1.3 eq) and 1 mL ofAcOH. The solution was allowed to stir at RT for 16 h. The reactionmixture was concentrated to give the oxime intermediate. The oxime wasdissolved in EtOH (20 mL) and borane-pyridine complex (0.74 g, 7.9 mmol)was added dropwise. After stirring at r.t for 20 min, the reactionmixture was concentrated in vacuo. The residue was redissolved in DCM(50 mL) and washed with water (3×20 mL). The organic layer was dried(Na₂SO₄) and concentrated to give 1.6 g (54%) of tert-butyl2-(3-bromophenyl)-1-(methoxyamino)propan-2-ylcarbamate (CD3; R¹=OMe,R⁴=Me). ¹H NMR (CDCl₃) δ 7.60-7.10 (m, 4H), 5.82 (s, 1H), 3.90 (s, 3H),3.70 (m, 2H) 1.80 (s, 3H), 1.40 (s, 9H). The crude compound was used inthe next step without further purification.

Alternative Method CD, Step 3:4-(3-Bromophenyl)-1-methoxy-4-methylimidazolidin-2-imine

tert-Butyl 2-(3-bromophenyl)-1-(methoxyamino)propan-2-yl carbamate (CD3;R¹=OMe, R⁴=Me) (1.6 g, 4.4 mmol) was dissolved in 25% TFA in DCM (25 mL)and the mixture was left stirring at RT for 1 h. The mixture wasconcentrated in vacuo. The residue was redissolved in CHCl₃ (20 mL) andwashed with 15% NaOH (10 mL). The aqueous layer was extracted with CHCl₃(3×10 mL). The combined organic layer was dried over MgSO₄ andconcentrated in vacuo. The residue was dissolved in EtOH (10 mL) andBrCN (0.096 g, 0.91 mmol) was added. After stirring at RT for 16 h, themixture was concentrated in vacuo. The residue was redissolved in CHCl₃(20 mL) and washed with 15% NaOH (10 mL). The aqueous layer wasextracted with CHCl₃ (3×10 mL). The combined organic layer was driedover MgSO₄ and concentrated to give 0.2 g (16%) of4-(3-bromophenyl)-1-methoxy-4-methylimidazolidin-2-imine (CD4; R¹=OMe,R⁴=Me) as a colorless oil. ¹H NMR (CDCl₃) δ 7.65-7.35 (m, 4H), 4.02 (s,3H), 3.98 (d, 1H), 3.91 (d, 1H), 1.94 (s, 3H).

Alternative Method CD, Step 4:4-(3-(3-Chlorophenyl)phenyl)-1-methoxy-4-methylimidazolidin-2-imine

A mixture of 4-(3-bromophenyl)-4-methyloxazolidin-2-imine (CD4; R¹=OMe,R⁴=Me) (0.027 g, 0.1 mmol, 1 eq), 3-chloro phenylboronic acid (0.023 g,0.13 mmol, 1.3 eq), FibreCat (0.020 g), anhydrous ethanol (2 mL), and 1NK₂CO₃ aqueous solution (0.12 mL, 0.12 mmol, 1.2 eq) was heated in amicrowave reactor (Emrys Optimizer) at 110° C. for 15 min. The mixturewas transferred to a prepacked column of Si-carbonate (2 g, 0.79mmol/g), which had been conditioned with MeOH/DCM (1:1). The column waseluted with 1:1 MeOH/DCM (3×3 mL) and the eluants were collected andconcentrated to give 0.008 g (25%) of4-(3-(3-chlorophenyl)phenyl)-1-methoxy-4-methylimidazolidin-2-imine(CD5; R¹=OMe, R⁴=Me, R²¹=3-ClC₆H₄) as a white solid. ¹H NMR (CDCl₃) δ7.75-7.60 (m, 5H), 7.58-7.42 (m, 3H), 4.00 (m, 2H), 3.97 (s, 3H), 1.97(s, 3H). MS (ESI) m/e 316.0, 318.0 (M⁺H)⁺, HPLC (A) R_(t)=5.64 min.

Method CE, Step 1

The synthesis of CE2 (R¹=R⁴=Me, R²¹=Br and R⁴=Me) was adapted from theprocedure of Spanu, P. et. al., Tet. Lett., 2003, 44, 671-675. Thus, toa solution of (S)-tert-butyl4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate(CE1; R¹=R⁶=Me, R²¹=Br) (0.24 g, 0.6 mmol, 1 eq) in THF (4 mL), LDA (2Min heptane/THF, 0.6 mL, 0.12 mmol, 2 eq) was added dropwise via asyringe at −78° C. After stirring at −78° C. for 30 min, a solution ofiodomethane (0.080 mL, 0.12 mmol, 2 eq) in THF (4 mL) was added dropwiseto form an orange-colored enolate solution. The mixture was stirred at−78° C. for 3 h. Water was added to quench the reaction and thesuspension was warmed to RT. The mixture was then partitioned betweenH₂O and Et₂O. The organic layer was separated and the aqueous layer wasextracted with Et₂O (3×25 mL).

The combined organic layers were washed with brine, dried (MgSO₄) andconcentrated to give 0.38 g of a brown oil. Chromatography on silica gelusing 50% EtOAc/hexanes as eluent gave 0.14 g (54%) of tert-butyl(4S,5R)-4-(3-bromophenyl)-1,4,5-trimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate(CE2; R¹=R⁴=Me, R²¹=Br and R⁶=Me) as a white solid. ¹HNMR (CDCl₃, 300MHz): δ 10.16 (s, 1H), 7.46 (m, 2H), 7.26 (m, 2H), 3.21 (s, 1H), 3.01(m, 3H), 3.02 (m, 1H), 1.51 (s, 12H), 1.17 (d, J=7.1 Hz, 3H). MS (ESI):MH⁺=441.7 HPLC (A) R_(t)=7.20 min.

Method CE, Step 2

A mixture of (S)-tert-butyl4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CE2; R¹=R⁴=Me, R⁶=Me, R²¹=Br) (0.25 g, 0.6 mmol),5-cyanothien-1-ylboronic acid (0.2 g, 1.3 mmol, 2 eq), Fibrecat (4.26%Pd, 0.7 g), and 1N aq. K₂CO₃ (0.5 mL) was heated at 110° C. in a 20 mLSmith process vial using the Emrys microwave synthesizer. After cooling,the reaction mixture was transferred to a pre-packed column ofSi-Carbonate column and eluted with with MeOH/CH₂Cl₂ (1:1). The eluentwas concentrated to give 0.32 g of a yellow oil, which was purified bysilica gel chromatography (20-50% EtOAc/hexanes to give 0.13 g (0.3mmol, 48% yield, syn:anti ratio: 5:1) of (S)-tert-butyl4-(3-(5-cyanothien-1-yl)phenyl)-1,4-dimethyl-6-oxotetrahydro-pyrimidin-2(1H)-ylidenecarbamateas a white solid. ¹HNMR (CDCl₃, 300 MHz): δ 10.15 (s, 1H), 7.58-7.53 (m,3H), 7.53-7.38 (m, 2H), 7.23 (m, 1H), 3.32 (s, 3H), 3.16 (m, 1H), 1.57(s, 9H), 1.23 (d, J=6.9 Hz, 3H). MS (ESI): MH⁺=438.7; M⁺−56=383.1. HPLCR_(t)=7.28 min (syn isomer).(S)-tert-Butyl4-(3-(5-cyanothien-1-yl)phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate(23 mg, 0.05 mmol) was treated with 1 mL of 30% TFA/CH₂Cl₂ at RT for 30min. The volatiles were removed in vacuo and the residue wasre-dissolved in acetonitrile (5 mL) and evaporated again to afford 17 mgof crude iminopyrimidinone as a yellow solid. The crude product waspurified by reverse phase HPLC (B) to provide 10 mg (60%) of(S)-6-(3-(5-cyanothien-1-yl)phenyl)-6-ethyl-2-imino-3-methyl-tetrahydropyrimidin-4(1M-one(CE3; R¹=R⁴=Me, R⁶=Me, R²¹=5-cyanothien-1-yl) as a white solid. ¹HNMR(CDCl₃, 300 MHz): δ 11.1 (brs, 1H), 10.0 (s, 1H), 7.58-7.53 (m, 3H),7.44 (m, 1H), 7.40-7.26 (m, 2H), 3.30 (m, 1H), 3.16(s, 3H), 1.60 (s,3H), 1.27 (d, J=7.2 Hz, 3H). MS (ESI): MH⁺=438.7; M+−56=339.1. HPLCR_(t)=7.24 min (syn isomer).

Method CF, Step 1.

To a solution of t-butylcarbamate (0.5 g, 4.3 mmol, 1 eq) in anhydrousTHF (5.0 mL) at RT was added NaH (0.17 g, 4.3 mmol, 1 eq). The mixturewas stirred at RT for 15 min. Then a solution of methyl isocyanate (0.3g, 4.2 mmol, 1 eq.) in anhydrous THF (5.0 mL) was added dropwise. Thereaction mixture was allowed to stir at 25° C. for 15 min. The mixturewas then poured into 30 mL of ice-water under vigorous stirring. Thereaction solution was extracted with Et₂O (2×25 mL). The organic layerswere combined and washed with brine (30 mL), dried (Na₂SO₄), andconcentrated in vacuo to give 0.42 g (50% yield) of tert-butylmethylcarbamothioylcarbamate CF1 (R¹=Me) as a white solid 1 HNMR (CDCl₃,300 MHz): δ 8.3 (br s, 1H), 3.19 (d, 3H, J=4.8 Hz), 1.8 (br s, 1H), 1.5(s, 9H).

Method CF, Step 2.

To a solution of an HCl salt of AB2 (R⁶=3-bromophenyl and R⁷=Me) (0.2 g,0.7 mmol) and CF1 (R¹=Me) in DMF (2 mL) at RT was added DIEA (0.5 mL,2.8 mmol, 4 eq) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide HCl(EDCI, 0.2 g, 1.0 mmol, 1.4 eq). After stirring at RT for 16 h, themixture was diluted with EtOAc (10 mL), washed with brine, dried(MgSO₄), and filtered. The filtrate was evaporated under reducedpressure to afford 0.34 g of crude product as a yellow oil which waspurified using silica gel chromatography by eluting with 20%EtOAc/hexanes to give 0.17 g (0.4 mmol, 60%) of (S)-tert-butyl4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate(CF2; R¹=R⁶=Me) as a white solid.

¹HNMR (CDCl₃, 300 MHz): δ 10.63 (s, 1H), 7.42 (m, 2H), 7.24 (m, 2H),3.21 (s, 3H), 3.2 (d, 1H, J=16.3 Hz), 2.87 (d, 1H, J=16.1 Hz), 1.65 (s,3H), 1.55 (s, 9H). MS (ESI): MH⁺=395.7, 398.7. HPLC R_(t)=7.11 min.

Method CF, Step 3.

A mixture of (S)-tert-butyl4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate(CF2; R¹=R⁶=Me) (0.25 g, 0.6 mmol), 5-chloro-2-hydroxyphenylboronic acid(R²¹=5-chloro-2-hydroxyphenyl; 0.2 g, 1.2 mmol, 2 eq), Fibrecat (4.26%of Pd, 0.7 g) and 1N aq. K₂CO₃ (0.5 mL) in dimethoxyethane (DME, 10 mL)or tert-butanol (10 mL) in a 20 mL Smith process vial equipped with stira bar was sealed and heated in an Emrys optimizer at 110° C. for 15 min.After cooling, the reaction mixture was transferred to a pre-packedSi-Carbonate column and eluted with MeOH/CH₂Cl₂ (1:1). The eluant wascollected and concentrated under reduced pressure to give 0.32 g of thecrude product as an oil. The crude product was purified by silica gelchromatography (20-50% EtOAc/hexanes gradient) to yield 0.13 g (0.3mmol, 48%) of (S)-tert-butyl4-(3-(3-chloro-6-hydroxyphenyl)-phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate(CF3; R¹=R⁶=Me, R²¹=3-chloro-6-hydroxyphenyl) as a white solid. ¹HNMR(CDCl₃, 300 MHz): δ 7.48-4.32 (m, 2H), 7.20 (m, 3H), 6.84 (m, 2H), 5.68(br s, 1H), 3.28 (d, J=15.7 Hz, 1H), 3.21 (s, 3H), 2.96(d, J=15.3 Hz,1H), 1.68 (s, 3H), 1.53 (s, 9H). MS (ESI): MH⁺=443.7, 445.7;M⁺-56=388.0. HPLC Rt (A)=6.99 min.

Method CF, Step 4.(S)-tert-butyl4-(3-(3-chloro-6-hydroxyphenyl)phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate(CF3; R¹=R⁶=Me, R²¹=3-chloro-6-hydroxyphenyl) (23 mg, 0.05 mmol) wastreated with 1 mL of 30% TFA/CH₂Cl₂ at RT for 30 min. The volatiles wereremoved in vacuo. The residue was redissolved in acetonitrile (5 mL) andevaporated again to afford 17 mg of the crude product as a yellow solid.The crude product was purified via reverse phase HPLC to provide 10 mg(60%) of(S)-6-(3-(3-chloro-6-hydroxy-phenyl)phenyl)-6-ethyl-2-imino-3-methyl-tetrahydropyrimidin-4(1″-one(CF4; R¹=R⁶=Me, R²¹=3-chloro-6-hydroxyphenyl) as a white solid. ¹HNMR(CDCl₃, 300 MHz): 611.4 (br s, 1H), 7.6-4.25 (m, 3H), 7.24-6.84 (m, 3H),3.68 (brs, 1H), 5.18 (brs, 1H), 3.39 (d, J=16.1 Hz, 1H), 3.20 (s, 3H),2.95(d, J=15.8 Hz, 1H), 1.74 (s, 3H). MS (ESI): MH⁺=344.1. HPLC (A)R_(t)=5.07 min.

Method CG, Step 1;

A solution of CG1 (R²¹=Br, 12.29 g, 45 mmol) and NaOH (1.93 g, 49 mmol)in MeOH (70 mL) and water (10 mL) was refluxed for 3 h. After removal ofMeOH under vacuum, the aqueous residue was adjusted to pH 3 and theresulting solid filtered off, dried under vacuum to give CG2 (R²¹=Br,11.41 g, 98%). ¹H NMR (400 MHz, CD₃OD) δ 8.49 (m, 1H), 8.27 (m, 1H),3.90 (s, 3H).

Method CG, Step 2;

A mixture of CG2 (R²¹=Br, 11.41 g, 44 mmol), EDCI (8.6 g, 45 mmol),dipropylamine (6.2 mL, 44.8 mmol), HOBt (6.0 g, 44.4 mmol) and NEt₃ (10mL, 72 mmol) in CH₂Cl₂ (100 mL) was stirred at RT for 48 h. The reactionwas washed with sat. NaHCO₃, water (1×), NH₄Cl (1×), water (1×), brine(1×), dried over MgSO₄, filtered and concentrated under vacuum. Theresulting material was subjected to silica gel chromatography (0%-40%EtOAc/hexanes) to give CG3 (R²¹=Br, R¹⁵=R¹⁶=Pr, 3.62 g, 24%).

Method CG, Step 3;

A mixture of CG3 (R²¹=Br, R¹⁵=R¹⁶=Pr, 3.6 g, 10.5 mmol), HN(Me)SO₂Me(1.4 mL, 16.3 mmol), Pd(OAc)₂ (355 mg, 1.58 mmol), Xantphos (1.41 g,2.44 mmol), Cs₂CO₃ (5.17 g, 15.8 mmol) in toluene (40 mL) was degassedunder a stream of N₂ for 10 min, then heated at 95° C. for 18 h. Thereaction was cooled to RT, filtered through celite, and the filtratepartitioned between EtOAc and water. The organic layer was washed withwater (1×), brine (1×), dried over MgSO₄, filtered, and evaporated undervacuum. The resulting residue was subjected twice to silica gelchromatography (0%→3% MeOH/CH₂Cl₂) to give CG4 (R²¹=N(Me)SO₂Me,R¹⁵=R¹⁶=Pr, 2.65 g, 68%).

Method CG, Step 4;

LiBH₄ (2 M THF, 8 mL, 16 mmol) was added to a solution of CG4(R²¹=N(Me)SO₂Me, R¹⁵=R¹⁶=Pr, 2.65 g, 7.15 mmol) in THF (40 mL) at 0° C.After 18 h at RT, the reaction was quenched with 1M HCl and extractedwith EtOAc. The organic layer was washed with brine (1×), dried overMgSO₄, filtered, and evaporated under vacuum. The resulting residue wassubjected to silica gel chromatography (0%) 5% MeOH/CH₂Cl₂) to give CG5(R²¹=N(Me)SO₂Me, R¹⁵=R¹⁶=Pr, 1.77 g, 72%).

Method CG, Step 5;

A mixture of CG5 (R²¹=N(Me)SO₂Me, R⁵=R¹⁶=Pr, 1.77 g, 5.17 mmol), sodiumazide (404 mg, 6.21 mmol), and PPh₃ (2.85 g, 10.87 mmol) in CCl₄ (5 mL)and DMF (20 mL) was stirred at 90° C. for 5 h, then at RT for 18 h. Thereaction was stirred with water (10 mL) for 10 min, then diluted withEt₂O. The organic layer was triturated with water, filtered, dried overMgSO₄, and evaporated under vacuum. The resulting material was directlyused in the next step (azide reduction).

Method CG, Step 6;

The product from method CG, step 5 was dissolved in EtOH (5 mL) andstirred in the presence of 10% Pd/carbon under an atmosphere of hydrogen(50 psi) for 18 h at RT. The reaction mixture was passed through aPTFE-filter, and the filtrate evaporated under reduced pressure. Theresulting material was subjected to preparative thin layerchromatography (5% MeOH/CH₂Cl₂) to give CG6 (R²¹=N(Me)SO₂Me, R¹⁵=R¹⁶=Pr,130 mg, 7.5% from CG5).

Method CG, Step 7;

A mixture of CG6 (R²¹=N(Me)SO₂Me, R¹⁵=R¹=Pr, 130 mg, 0.38 mmol),1,3-di(tert-butoxycarbonyl)-2-methylisothiourea (110 mg, 0.38 mmol),NEt₃ (55 μL, 0.38 mmol) in DMF (1.5 mL) was stirred at RT for 48 h.After removal of the volatiles in vacuo, the resulting material wassubjected to preparative thin layer chromatography (5% MeOH/CH₂Cl₂ aseluent). The resulting intermediate (140 mg, 0.24 mmol) was treated with50% TFA/CH₂Cl₂ at RT for 3 h, followed by removal of all volatiles undervacuum to give CG7 (R²¹=N(Me)SO₂Me, R¹⁵=R¹⁶=Pr, 140 mg, 74% from CG6).

Method CG, Step 8;A mixture of CG7 (R²¹=N(Me)SO₂Me, R¹⁵=R¹⁶=Pr, 120 mg, 0.24 mmol), benzil(50 mg, 0.24 mmol) and NEt₃ (134 μL, 0.96 mmol) in EtOH (5 mL) washeated at 100° C. for 18 h. After evaporating all volatiles, the residuewas partitioned between water and CH₂Cl₂. The organic layer was washedwith brine (1×), dried over MgSO₄, filtered and evaporated. Theresulting material was subjected to preparative thin layerchromatography (10% MeOH/CH₂Cl₂ as eluent) to give CG8 (R²¹=N(Me)SO₂Me,R¹⁵=R¹⁶=Pr, R³=R⁴=Ph, 69 mg, 50%) as the formate salt. ¹H NMR (400 MHz,CDCl₃) δ 7.10-7.40 (m, 13H), 4.72 (m, 2H), 3.34 (m, 2H), 3.08 (s, 3H),3.00 (m, 2H), 2.60 (s, 3H), 1.59 (m, 2H), 1.39 (m, 2H), 0.92 (m, 3H),0.64 (m, 3H); LCMS: 576.3 (M⁺H).

A solution of 0.35 mL of 1M BBr₃ in DCM (0.35 mmole) was added dropwiseto a solution of CH1 (52 mg, 0.11 mole) in 1.5 mL anhydrous DCM in icebath. The reaction solution was stirred in ice bath for 10 min. and 2hrs at RT. The reaction was quenched with 5 mL MeOH in ice bath. Afterconcentration the crude was purified on C18 reverse phase column to giveCH2 (37.3 mg, 67. % yield) as a formate.

A solution of CI1 (20 mg as a formate; 0.042 mmole) in 4 mL of DCM wastreated with mCPBA (0.42 mmole) at RT for 2 hrs. The crude mixture waspurified on C18 reverse phase column to give compound C12.

To a solution of CJ1 (R¹=R⁶=Me; 324 mg, 0.87 mmole) in 2.5 mL CHCl₃ and2.5 mL HOAc in ice bath was added NBS (312 mg, 1.75 mmole) and thereaction mixture was stirred at RT. Upon reaction completion, the crudemixture was diluted with DCM, and washed with saturated aqueous Na₂S₂O₃,aqueous NaHCO₃ and brine. The crude was purified on flash column to givea product which was treated with 50% TFA in DCM to give CJ2 (R¹=R⁶=Me220 mg, 56. % yield) after evaporation.

Method CK, Step 1;

Similar to a literature procedure (Moloney et al., J. Med. Chem. 1997,2347-2362), methyl bromomethylbenzoate (7.00 g, 30.5 mmol) was added toa suspension of CK1 (R³=R⁴=Ph, 7.00 g, 27.8 mmol) and K₂CO₃ (3.85 g,27.8 mmol) in DMF (50 mL) at RT. After 18 h, the reaction mixture wasdiluted with water and extracted with CH₂Cl₂ (3×). The combined organiclayers were washed with NaHCO₃ (1×), water (3×), dried over MgSO₄,filtered and concentrated under vacuum to give compound CK2 (12.7 g,100%)

Method CK, Step 2;

Compound CK3 was obtained from CK2 using method BK, step 3.

Method CK, Step 3;

CK3 (1.18 g, 2.83 mmol) in THF (15 mL) and 2 N LiOH (4 mL, 8 mmol) wasstirred overnight at RT. The mixture was quenched with 6 N HCl (2 mL, 12mmol) and then partitioned between water and EtOAc. The dried EtOAclayer was concentrated in vacuo and the residue subjected toreverse-phase HPLC (gradient from 10% 95% CH₃CN/H₂O with 0.1% HCO₂H, 30mL/min flow rate on a preparative C18 reverse-phase column) to affordCK4.

Method CK, Step 4;

Compounds CK5 were obtained from CK4 using method G, step 2.

Method CK, Step 5;Compounds CK6 were obtained from CK5 using method A, step 3.

Method CL, Step 1;

CL2 was obtained from CL1 (3-chlorophenyl boronic acid) following methodAW.

Method CL, Step 2;

Trimethylsilyldiazomethane (2 M hexanes, 2.5 mL, 5.0 mmol) was added toa solution of LDA (freshly prepared from DIPA and ^(n)BuLi) in THF at−78° C. After 30 min at −78° C., a solution of aldehyde CL2 (900 mg,4.13 mmol) in THF (5 mL) was added and the reaction slowly warmed to RTover 3 h. The reaction was quenched with water, then extracted with Et₂O(2×100 mL). The combined organic layers were washed with brine (1×),dried over MgSO₄, filtered, and evaporated under vacuum. The resultingmaterial was subjected to silica gel chromatography (100% hexanes) togive CL3 (752 mg, 86%). ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.65 (m, 8H),3.08 (s, 1H).

Method CL, Step 3;

A mixture of CL3 (202 mg, 0.95 mmol), aryl bromide (Ar=3,5-pyrimidinyl,181 mg, 1.14 mmol), Pd(dba)₂ (27 mg. 47.5 μmol), PPh₃ (25 mg, 95 μmol),CuI (18 mg, 95 μmol) and DIPA (400 μL, 285 μmol) in DMF (2 mL) wasdegassed for 10 min under a stream of N₂, then heated at 100° C. for 30min in a Smith Synthesizer microwave. The reaction was cooled to RT,filtered and diluted with EtOAc. The organic layer was washed with water(1×), brine (1×), dried over MgSO₄, filtered, and evaporated undervacuum. The resulting material was subjected to silica gelchromatography (0→20% EtOAc/hexanes) to give CL4 (R³=3,5-pyrimidinyl,220 mg, 80%).

Method CL, Step 4;

A mixture of CL4 (R³=3,5-pyrimidinyl, 210 mg, 0.72 mmol), KMnO₄ (297 mg,1.88 mmol), tetrabutylammonium bromide (TBAB, 55 mg, 0.17 mmol) in AcOH(263 μL) and CH₂Cl₂ (5 mL) was stirred for 3 h at RT. The reactionmixture was filtered through a plug of silica gel, eluting with MeOH,and the filtrate was concentrated under vacuum. The residue wassubjected to preparative thin layer chromatography (5% MeOH/DCM) to giveCL5 (R³=3,5-pyrimidinyl, 154 mg, 66%).

Method CL, Step 5;Diketone CL5 was converted into CL6 as described in Method CG, step 8.LCMS (CL6, R³=3,5-pyrimidinyl): 378.2 (M⁺H).

Method CM, Step 1To a round bottom flask were added CM1 (R¹=Me, R³=Ph; 500 mg, 1.22mmol), methanol (20 mL) and 10% Pd/C (200 mg). The mixture washydrogenated by a hydrogen balloon for 3 hour 40 min at stirring. Afterfiltration, the concentrated residue was purified by Analogix flashcolumn chromatography (EtOAc/Hexane=0%-50%) to produce CM2 (R¹=Me,R³=Ph; 443 mg, 92%) as white solid. Observed MW (M⁺H) 381.2. (400 MHz,CD₃OD): δ=9.13 (s, br, 1H), 7.36-7.26 (m, 5H), 7.09 (m, 1H), 6.68-6.57(m, 3H), 3.13 (s, 3H), 1.49 (s, 9H).

To an Ace pressure tube were added CN1 (R³=phenyl; R¹=Me; 100 mg, 0.290mmol), bis(pinacolato)diboron (81.0 mg, 0.319 mmol), KOAc (85.0 mg, 0.87mmol), PdCl₂(dppf)₂.CH₂Cl₂ (24 mg, 0.029 mmol) and anhydrous DMSO (1.0mL). The reaction was then heated to 120° C. (oil bath temperature) atstirring for 2 hour 15 min. After cooling down to RT, the reaction wereadded 3,5-dibromo pyridine (206 mg, 0.87 mmol), anhydrous DMSO (1.0 mL)and 1M aq. K₂CO₃ (1.45 mL, 1.45 mmol). The reaction was then heated to120° C. at stirring for 45 min. After cooling down to RT, the reactionwas poured to cold water. The aqueous layer was extracted by DCM (3×50mL) and the combined organic layer was dried over Na₂SO₄. Theconcentrated residue was purified first by preparative TLC (7MNH₃/MeOH:DCM=1:10) and then preparative HPLC (reverse phase, C-18column, 0.1% HCOOH/CH₃CN: 0.1% HCOOH/H₂O=10%-100%) to afford the desiredproduct CN2 (formic acid salt; R³=phenyl; R¹=Me; R²¹=3′-(5-bromopyridyl;53.5 mg, 40%) as a white solid. Observed MW (M⁺H) 421.1. (400 MHz,CD₃OD): δ=8.83-8.50 (m, br. 2H), 8.21 (s, 1H), 7.65 (m, 2H), 7.50 (m,2H), 7.37 (m, 5H), 3.22 (s, 3H).

A microwave tube was charged with CO1 (R¹=Me, R²=H; R³=cyclopropyl, n=0)(30 mg, 0.097 mmol), PS-Ph₃P—Pd (49 mg, 0.12 mmol), and R²¹SnBu₃(R²¹=2-pyrazinyl) (43 mg, 0.12 mmol) as a solution in 1 mL of PhCF₃. Thetube was sealed, and evacuated and back-filled with N₂ (5×). The mixturewas then exposed to microwave irradiation (110° C., 30 min). Theresulting mixture was filtered with copious MeOH washes. Concentrationof the filtrate gave a crude product that was subjected to RP-HPLC togive CO₂ (R¹=Me, R²=H; R³=c-Pr, n=0, R²¹=2-pyrazinyl) as a formate salt(12 mg, 0.063 mmol, 35%). LCMS R_(t)=3.58 min, m/e=308.2 (M⁺H).

Method CP; Step 1: 1,4,2-Diazaphospholidin-5-one,2-methoxy-1-methyl-3,3-diphenyl-2-oxide (CP3)

Using methods similar to those described by 1. V. Konovalova et al.(Zhurnal Obshchei Khimii, 50(7), 1653-1654), 1.0 equivalent ofphosphorisocyanatidous acid dimethyl ester (CP2), is added to a solutionof benzophenone imine (CP1) in toluene and the mixture is warmed toreflux for 4 h. Removal of solvent and purification by flashchromatography provides the title compound (CP3).

Method CP, Step 2: 1,4,2-Diazaphospholidin-5-thione,2-methoxy-1-methyl-3,3-diphenyl-2-oxide (CP4)

To a solution of CP3 in toluene (or xylene) is added Lawesson's reagent(1.2 equivalents), and the mixture is stirred at reflux for 2 h. Themixture is cooled and poured into cold water. The organic phase is dried(MgSO₄) and filtered, and solvent is removed. The crude product ispurified by flash chromatography to provide the title compound (CP4).

Method P1, Step 3: 1,4,2-Diazaphospholidin-5-imine,2-methoxy-1-methyl-3,3-diphenyl-2-oxide (CP5)

Using a route similar to that described in Method A, step 3, CP4 is usedto prepare the title compound (CP5).

As a variant of Method CP, benzophenone imine (CP1) is treated with 1.0equivalent of phosphorisocyanatidous acid dimethyl ester[(CH₃O)₂P—N═C═S], giving directly CP4, which is coverted to CP5 asdescribed in Method CP, Step 3.

Method CO, Step 1: 1,4,2-Diazaphospholidin-5-thione,2-methoxy-1-methyl-3-methyl-3-(4-chloro)phenyl-2-oxide (CQ2)

Using an approach similar to that described by R. Merten et al. [(Chem.Ber., 102, 2143 (1969)], methylisothiocyanate (1.2 equivalents) is addedto a solution of dimethyl [1-amino-1-(4-chloro)phenyl]ethylphosphonate(CQ1) in chloroform and the mixture is gradually warmed to reflux. After2 h at reflux, the mixture is cooled and solvent is removed byevaporation. Purification of the crude product by flash chromatographyprovides the title compound.

Method CQ, Step 2: 1,4,2-Diazaphospholidin-5-imine,2-methoxy-1-methyl-3-methyl-3-(4-chloro)phenyl-2-oxide (CQ3)

Using a route similar to that described in Method A, step 3, CQ2 is usedto prepare the title compound.

Method CR, Step 1: 1,4,2-Diazaphospholidin-5-one,2-methoxy-1-methyl-3-methyl-3-(4-bromo)phenyl-2-oxide (CR2)

Using an approach similar to that described by R. Merten et al. [(Chem.Ber., 102, 2143 (1969)), methylisocyanate (1.2 equivalents) is added toa solution of dimethyl [1-amino-1-(4-bromo)phenyl]ethylphosphonate (CR1)in chloroform and the mixture is gradually warmed to reflux. After 2 hat reflux, the mixture is cooled and solvent is removed by evaporation.Purification of the crude product by flash chromatography provides thetitle compound (CR2).

Method CR, Step 2: 1,4,2-Diazaphospholidin-5-thione,2-methoxy-1-methyl-3-methyl-3-(4-bromo)phenyl-2-oxide (CR3)

To a solution of CR2 in toluene or xylene is added Lawesson's reagent(1.2 equivalents), and the mixture is stirred at reflux for 2 h. Themixture is cooled and poured into cold water. The organic phase is dried(MgSO₄) and filtered, and solvent is removed. The crude product ispurified by flash chromatography to provide the title compound.

Method CR, Step 3: 1,4,2-Diazaphospholidin-5-imine,2-methoxy-1-methyl-3-methyl-3-(4-bromo)phenyl-2-oxide (CR4)

Using a route similar to that described in Method A, step 3, CR3 is usedto prepare the title compound.

Method CS, Step 1: 1,4,2-Diazaphospholidin-5-thione,2-methoxy-4-(4-methoxy)phenylmethyl)-1-methyl-3-phenylmethyl-2-oxide(CS2)

Using an approach similar to that described by R. Merten et al. [(Chem.Ber., 102, 2143 (1969)), methylisothiocyanate (1.2 equivalents) is addedto a solution of dimethyl[1-(4-methoxy)phenylmethylamino-2-(4-bromo)phenyl]ethylphosphonate (CS1)in chloroform and the mixture is gradually warmed to reflux. After 2 hat reflux, the mixture is cooled and solvent is removed by evaporation.Purification of the crude product by flash chromatography provide thetitle compound.

Method CS, Step 2: 1,4,2-Diazaphospholidin-5-imine,2-methoxy-4-(4-methoxy)phenylmethyl)-1-methyl-3-phenylmethyl-2-oxide(CS3)

Using a route similar to that described in Method A, step 3, CS2 is usedto prepare the title compound.

Method CS, Step 3: 1,4,2-Diazaphospholidin-5-imine,2-methoxy-1-methyl-3-phenylmethyl-2-oxide (CS4)

A solution of CS3 in methanol is hydrogenated at 1 atm in the presenceof 5 mol % Pd/C, yielding the title compound after filtration andpurification by flash chromatography.

Method CT, Step 1:Dimethyl-[(4-bromophenyl)-1-isothiocyanato]ethylphosphonate

To a mixture of CT1 in DCM and 0.1 N aqueous sodium bicarbonate (1.0equivalent) is added thiophosgene (1.5 equivalents), and the mixture isstirred for 4 h at RT. Water is added, and the organic phase is dried(MgSO₄), filtered and concentrated to give the product CT2 which is usedwithout purification.

Method CT, Step 2: 1,4,2-Diazaphospholidin-5-thione,2-methoxy-1-ethyl-3-(4-bromo)phenyl-2-oxide (CT3)

To a solution of CT2 in acetonitrile is added ethylamine (2 equivalents)and diisopropylethylamine (2 equivalents) and the solution is slowlywarmed to reflux for 2 h. After removal of solvent, the product ispurified by flash chromatography to give the title product.

Method CT Step 3: 1,4,2-Diazaphospholidin-5-imine,2-methoxy-1-ethyl-3-(4-bromo)phenyl-2-oxide (CT4)

Using a route similar to that described in Method A, step 3, CT3 is usedto prepare the title compound.

Method CU, Step 1: 1,5,2-Diazaphosphorine-6(1H)-thione,1-methyl-2-methoxy-3-phenyl-2-oxide (CU2)

Using an approach similar to that described by R. Merten et al. [(Chem.Ber., 102, 2143 (1969)), methylisothiocyanate (1.2 equivalents) is addedto a solution of dimethyl (2-amino-1-phenyl)ethylphosphonate (CU1) inchloroform and the mixture is gradually warmed to reflux. After 2 h atreflux, the mixture is cooled and solvent is removed by evaporation.Purification of the crude product by flash chromatography provides thetitle compound.

Method CU, Step 2: 1,5,2-Diazaphosphorine-6(1H)-imine,1-methyl-2-methoxy-3-phenyl-2-oxide (CU3)

Using a route similar to that described in Method A, step 3, CU2 is usedto prepare the title compound.

Method CV, Step 1: Dimethyl (2-isothiocyanato-1-phenyl)ethylphosphonate(CV2)

To a mixture of CV1 in methylene chloride and 0.1 N aqueous sodiumbicarbonate (1.0 equivalent) is added thiophosgene (1.5 equivalents),and the mixture is stirred for 4 h at RT. Water is added, and theorganic phase is dried (MgSO₄), filtered and concentrated to give theproduct which is used without purification.

Method CV, Step 2: 1,5,2-Diazaphosphorine-6(1H)-thione,1-cyclopropyl-2-methoxy-3-phenyl-2-oxide (CV3)

To a solution of CV2 in acetonitrile is added cyclopropylamine (2equivalents) and diisopropylethylamine (2 equivalents) and the solutionis heated at reflux for 2 h. After removal of solvent, the product ispurified by flash chromatography to give the title product.

Method CV Step 3: 1,4,2-Diazaphospholidin-5-imine,2-methoxy-1-cyclopropyl-3-(4-bromo)phenyl-2-oxide (CV4)

Using a route similar to that described in Method A, step 3, CV3 is usedto prepare the title compound.

Method CW; Step 1: Boc-1,5,2-diazaphosphorine-5-imine,2-methoxy-1-methyl-4-(3-arylphenyl)-2-oxides (CW2)

Reaction of tert-butyl methylcarbamothioylcarbamate with CW1 (R⁶=Me)using EDCI and DIEA in DMF affords CW2 (R⁶=Me) after purification.

Method CW; Step 2: 1,5,2-Diazaphosphorine-5-imine,2-methoxy-1-methyl-4-(3-(m-cyanopheny)phenyl)-2-oxides (CW3)

Following the procedure of Sauer, D. R. et al, Org. Lett., 2004, 6,2793-2796, Suzuki reaction of CW2 (R⁶=Me) with aryl boronic acids usingpolymer-support Pd catalysts such as Fibre Cat or PS-PPh3-Pd undermicrowave heating conditions provides CW3 (R⁶=Me and R²¹=m-CN-Ph) of theinvention after subsequent Boc-deprotection.

Method CX, Step 1,(S)-2-(tert-Butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylicacid

To a solution of (S)-tert-butyl4-(furan-2-yl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamateCX1 (R⁶=Me) (1.12 g, 3.64 mmol, prepared using Method CF) in DCM (7 mL)was added MeCN (7 mL) and H₂O (10.5 mL), followed by RuCl₃-H₂O (7.6 mg,0.036 mmol, 1 mol %), and NalO₄ (11.6 g, 54.2 mmol, 15 eq). The mixturewas stirred at RT for 2 h. The mixture was diluted with DCM (100 mL) andthe organic layer was separated, dried (Na₂SO₄), and concentrated togive 0.90 g (86%) of(S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylicacid CX2 (R⁶=Me) as a brown solid. ¹H NMR (CD₃OD): δ 3.17 (s, 3H), 3.02(m, 2H), 1.63 (s, 9H), 1.57 (s, 3H).

Method CX, Step 2,(6S)-2-Imino-3,6-dimethyl-6-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-tetrahydropyrimidin-4(1H)-one(CX3)

To a solution of(S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylicacid (CX2, R⁶=Me, 0.035 g, 0.12 mmol) in DMF (0.24 mL) was added TBTU(0.040 mg, 0.12 mmol, 1 eq), HOBt (0.0035 mg, 0.024 mmol, 0.2 eq), andDIEA (0.107 mL, 0.60 mmol, 5 eq). The mixture was stirred at RT for 10min and then N′-hydroxy-3-(trifluoromethyl)benzamidine (0.028 mg, 0.13mmol, 1.1 eq) was added. After stirring for another 2 h, the reactionmixture was diluted with EtOAc (20 mL), washed with H₂O (10 mL) andsaturated brine (10 mL), and concentrated in vacuo. The crude residuewas dissolved in THF (0.4 mL) and then TBAF (1M in THF, 0.099 mL, 0.9eq) was added. The mixture was stirred at RT for 2 h. EtOAc (20 mL) wasadded to the reaction mixture, which was washed with H₂O (10 mL) andsaturated brine (10 mL), and concentrated in vacuo. The residue wastreated with 30% TFA/DCM (1 mL) at RT for 1. The reaction mixture wasconcentrated in vacuo and the crude product was purified on reversephase HPLC (B) to give 0.015 g (26%) of(6S)-2-imino-3,6-dimethyl-6-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-tetrahydropyrimidin-4(1H)-one(CX3; R⁶=Me, R⁷=3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)) asa white solid. ¹H NMR (CD₃OD): δ 8.40 (m, 2H), 8.04 (d, 1H, J=6.9 Hz),7.90 (t, 1H, J=8.1 Hz), 3.81 (m, 2H), 3.39 (s, 3H), 1.82 (s, 3H). MS(ESI): MH⁺=354.2, HPLC (A) R_(t)=6.234 min.

(S)-2-(tert-Butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide

To a solution of(S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylicacid CX2 (R⁶=Me) (0.357 g, 1.25 mmol) in 1:5 MeOH/toluene (3 mL) wasadded TMSCHN₂ (2M in hexane, 1.9 mL, 3.8 mmol, 3 eq). The mixture wasstirred at RT for 2 h. The mixture was concentrated in vacuo to give0.37 g (100%) of (S)-methyl2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylateas a brown solid. ¹H NMR (CDCl₃): δ 8.80 (s, 1H), 3.70 (s, 3H), 3.14 (s,1H), 2.79 (s, 2H), 1.53 (s, 9H), 1.50 (s, 3H).To a solution of (S)-methyl2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylate(0.074 g, 0.25 mmol) in EtOH (0.5 mL) was added NH₂NH₂ (0.023 mL, 0.75mmol, 3 eq) and the mixture was stirred at RT for 4 h. The mixture wasconcentrated in vacuo to give 0.074 g (100%) of(S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide(CY1, R⁶=Me) as a yellow solid. ¹H NMR (CDCl₃) δ 8.95 (s, 1H), 3.11 (s,3H), 2.28 (m, 2H), 1.50 (s, 9H), 1.47 (s, 3H).

3-(5-((S)-2-Imino-1,4-dimethyl-6-oxo-hexahydropyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)benzonitrile

To a solution of(S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide(CY1; R⁶=Me, 0.037 g, 0.12 mmol) in DCM (0.3 mL) at 0° C. was added Et₃N(0.035 mL, 0.24 mmol, 2 eq) followed by 3-cyanobenzoyl chloride (0.027g, 0.16 mmol, 1.3 eq). The mixture was stirred at RT for 6 h. Themixture was diluted with DCM (20 mL), washed with H₂O (10 mL) andsaturated brine (10 mL), and concentrated in vacuo. The residue was thentreated with TsCl (0.035 g, 0.18 mmol, 1.5 eq), Et₃N (0.046 mL, 0.31mmol, 2.6 eq), and DMAP (0.002 g, 0.016 mmol, 0.13 eq) in DCM (0.25 mL)at RT for 16 h. The mixture was diluted with DCM (20 mL), washed withH₂O (10 mL) and saturated brine (10 mL), and concentrated in vacuo. Theresidue was treated with 30% TFA/DCM (1 mL) at RT for 1 h. The mixturewas concentrated in vacuo and the residue was purified on reverse phaseHPLC (B) to give 0.006 g (12%) of3-(5-((S)-2-imino-1,4-dimethyl-6-oxo-hexahydropyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)benzonitrileas a white solid (CZ1; R⁶=Me). ¹HNMR (CD₃OD, 300 MHz): δ 8.49 (m, 2H),8.12 (d, 1H), 7.92 (t, 1H), 3.75 (m, 2H), 3.36 (s, 3H), 1.82 (s, 3H). MS(ESI): MH⁺=311.2, HPLC (A) R_(t)=4.175 min.

(S)-6-(5-(3-Chlorophenylamino)-1,3,4-oxadiazol-2-yl)-2-imino-3,6-dimethyl-tetrahydropyrimidin-4(1H)-one

To a solution of(S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide(CY1, R⁶=Me, 0.030 g, 0.10 mmol) in DCM (0.25 mL) was added3-chlorophenylisocyanate (0.015 mL, 0.20 mmol, 2 eq). The mixture wasstirred at RT for 3 h and volatiles were then removed in vacuo. Theresidue was treated with TsCl (0.020 g, 0.10 mmol, 1 eq), Et₃N (0.083mL, 0.60 mmol, 6 eq), and DMAP (0.002 g, 0.016 mmol, 0.16 eq) in DCM(0.25 mL) at RT for 16 h. The mixture was diluted with DCM (20 mL),washed with H₂O (10 mL) and saturated brine (10 mL), and concentrated invacuo. The residue was treated with 30% TFA/DCM (1 mL) at RT for 1 h.The mixture was concentrated in vacuo and the residue was purified onreverse phase HPLC (B) to give 0.006 g (10%) of(S)-6-(5-(3-chlorophenylamino)-1,3,4-oxadiazol-2-yl)-2-imino-3,6-dimethyl-tetrahydropyrimidin-4(1H)-one(DA1; R⁶=Me). ¹HNMR (CD₃OD, 300 MHz): 67.78 (t, 1H), 7.47 (m, 2H), 7.17(dt, 1H), 3.53 (m, 2H), 3.36 (s, 3H), 1.78 (s, 3H). MS (ESI): MH⁺=335.3,HPLC (A) R_(t)=5.710 min.

Method DB, Step 1; (1-(3-Bromophenyl)ethylidene)cyanamide (DB1, R⁴=Me)

Following the procedure of Cuccia, S. J.; Fleming, L. B.; France, D. J.Synth. Comm. 2002, 32 (19), 3011-3018: 3-Bromoacetophenone (2.0 g, 10mmol, 1 eq), was dissolved in 20 mL DCM. A 1.0 N solution of titaniumtetrachloride in DCM (20 mL, 20 mmol, 2 eq) was added dropwise over 15min and the resulting mixture was stirred at 25° C. for 1 h.Bis-trimethylsilylcarbodiimide (5.0 mL, 22 mmol, 2.2 eq) in 5 mL of DCMwas added over 15 min and the reaction was stirred for 16 h under argon.The reaction was poured onto 200 mL of an ice/water mixture andextracted with 3×200 mL of DCM. The combined organic phase was driedover MgSO₄, filtered, and concentrated to give 2.3 g (100%) of(1-(3-bromophenyl)ethylidene)cyanamide (DB1, R⁴=Me) as a white solid: ¹HNMR (CDCl₃) δ 8.16 (t, J=1.8 Hz, 1H), 7.94 (dd, J=1.7, 1.1 Hz, 1H), 7.76(dd, J=1.7, 1.1 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 2.82 (s, 3H).

Method DB, Step 2;5-(3-Bromophenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine (DB2, R⁴=Me)

To a solution of the HCl salt of methylhydroxylamine (0.19 g, 2.2 mmol,1 eq) in ethanol (25 mL) at 25° C. was added a 21% solution of NaOEt inethanol (0.75 mL, 2.0 mmol, 0.9 eq) followed by (1-(3-bromophenyl)ethylidene) cyanamide (0.50 g, 2.2 mmol, 1 eq). After stirring at 25° C.for 10 min, the solvent was removed in vacuo. The residue wasredissolved in CH₂Cl₂ (25 mL), the mixture was filtered, and the solventwas removed in vacuo to give 0.5 g (83%) of5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine (DB2, R¹=Me,R⁴=Me) as a colorless oil: ¹H NMR (CDCl₃) δ 7.63 (t, J=1.8 Hz, 1H),7.52. (dd, J=2.0, 1.1 Hz, 1H), 7.38 (dd, J=2.0, 1.1 Hz, 1H), 7.29 (t,J=7.9 Hz, 1H), 3.28 (s, 3H), 1.88 (s, 3H). MS (ESI) m/e 270.0, 272.0(M⁺H)⁺.

Method DB, Step 3;5-(3-(3-Chlorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

To a solution of5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine (25 mg, 0.093mmol) and 3-chlorophenyl boronic acid (17 mg, 0.11 mmol) in ethanol (1mL) was added a 1 M aqueous solution of K₂CO₃ (0.22 mL, 0.22 mmol) andPS-PPh₃-Pd (46 mg, 0.0046 mmol). The sample was heated in an EmrysOptimizer Microwave at 110° C. for 10 min. The resin was filtered offand rinsed alternately three times with CH₂Cl₂ (5 mL) and CH₃OH (5 mL).The combined filtrates were concentrated and the residue was purified byreverse phase prep-HPLC to give 12.3 mg (44%) of5-(3-(3′-chlorophenyl)-phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine(DB3; R¹=Me, R⁴=Me, R²¹=3-chlorophenyl) as a colorless oil: ¹H NMR(CDCl₃) δ 7.69 (s, 1H), 7.58 (m, 2H), 7.49 (m, 3H), 7.37 (m, 2H), 3.29(s, 3H), 1.94 (s, 3H). MS (ESI) m/e 302.0, 304.0 (M⁺H)⁺.

Using a similar procedure, the following compounds were also prepared.

5-(3-(3-Methoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CDCl₃) δ 7.72 (s, 1H), 7.62 (dt, 1H), 7.49 (m, 2H), 7.38 (t,J=8.2 Hz, 1H), 7.20 (m, 1H), 7.14 (t, 1H), 6.93 (m, 1H), 3.88 (s, 3H),3.27 (s, 3H), 1.95 (s, 3H). MS m/e 298.1 (M⁺H)

5-(3-(2,5-Dimethoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CDCl₃) δ 7.67 (s, 1H), 7.57 (m, 1H), 7.45 (m, 2H), 6.92 (m, 3H),3.82 (s, 3H), 3.77 (s, 3H), 3.27 (s, 3H), 1.95 (s, 3H). MS m/e 328.1(M⁺H)

5-(3-(3-Fluorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CDCl₃) δ 7.71 (s, 1H), 7.60 (m, 1H), 7.50 (m, 2H), 7.41 (m, 2H),7.31 (m, 1H), 7.08 (m, 1H), 3.29 (s, 3H), 1.94 (s, 3H). MS m/e 286.0(M⁺H)

5-(3-(3-Trifluoromethoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CDCl₃) δ 7.70 (s, 1H), 7.59 (m, 1H), 7.55 (m, 1H), 7.50 (m, 2H),7.46-7.48 (m, 2H), 7.26 (m, 1H), 3.29 (s, 3H), 1.95 (s, 3H). MS m/e352.1 (M⁺H)

5-(3-(3-Pyridyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CD₃OD) δ 9.17 (s, 1H), 8.84 (m, 2H), 8.08 (m, 1H), 7.99 (s, 1H),7.88 (m, 1H), 7.72 (m, 2H), 3.37 (s, 3H), 2.00 (s, 3H). MS m/e 269.1(M⁺H)

5-(3-(3,5-Dichlorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CDCl₃) δ 7.66 (s, 1H), 7.54 (m, 1H), 7.52 (m, 2H), 7.47 (m, 2H),7.38 (m, 1H), 3.30 (s, 3H), 1.94 (s, 3H). MS m/e 336.1 (M⁺H)

5-(3-(2-Chlorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CDCl₃) δ7.59 (m, 1H), 7.50 (m, 4H), 7.34 (m, 3H), 3.28 (s, 3H),1.95 (s, 3H). MS m/e 302.1 (M⁺H)

5-(3-(3-Chloro-4-fluorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CDCl₃) δ 7.65 (m, 2H), 7.48-7.54 (m, 4H), 7.22 (m, 1H), 3.30 (s,3H), 1.94 (s, 3H). MS m/e 320.1 (M⁺H)

Method DC, Step 1, 5-(3-Bromophenyl)-5-methylimidazolidine-2,4-dione

A mixture of 3-bromoacetophenone (10 g, 50 mmol), KCN (8.16 g, 130 mmol,2.5 eq) and (NH₄)₂CO₃ (21.7 g, 225 mmol, 4.5 eq) in EtOH/H₂O (1:1, 110mL) was heated at 60° C. for 16 h. The reaction mixture was cooled to 0°C. The resulting precipitate was filtered, washed with water, hexane,and then dried to give 12.6 g (93%) of5-(3-bromophenyl)-5-methylimidazolidine-2,4-dione as an off-white solid(DC1; R⁶=Me).

¹H NMR (CD₃OD) δ 7.64 (s, 1H), 7.45 (t, J=9.7 Hz, 2H), 7.26 (t, J=7.6Hz, 1H), 1.68 (s, 3H).

Method DC, Step 2, 2-Amino-2-(3-bromophenyl)propanoic acid

5-(3-Bromophenyl)-5-methylimidazolidine-2,4-dione (DC1; R⁶=Me) (1.5 g,5.6 mmol) was dissolved in 15 mL of 1N KOH, heated to 185° C. in amicrowave reactor (Emrys Optimizer) for 2 h. Afterward, the mixture wascarefully acidified using conc. HCl to pH ˜2. The mixture was extractedonce with Et₂O (20 mL). The aqueous layer was concentrated in vacuo togive 1.6 g (100%) of 2-amino-2-(3-bromophenyl)-2-propanoic acid (DC2;R⁶=Me) as an off white solid. ¹H NMR (CD₃OD) δ 7.75 (t, J=2.0, 1H), 7.66(m, 1H), 7.56 (m, 1H), 7.45 (t, J=8.1 Hz, 1H), 1.99 (s, 3H).

Method DC, Step 3, 2-(3-Bromophenyl)-2-(tert-butoxycarbonyl)propanoicacid

To a solution of 2-amino-2-(3-bromophenyl)-propanoic acid (DC2; R⁶=Me)(10.5 g, 43 mmol) in 1N KOH (105 mL) and dioxane (70 mL) at 0° C. wasadded (Boc)₂O (20.6 g, 95 mmol, 2.2 eq). The mixture was stirred at RTfor 16 h. The reaction mixture was concentrated to 100 mL. EtOAc (100mL) was added and the mixture was cooled to 0° C. After acidifying with2N KHSO₄ to pH 2-3, the aqueous layer was extracted with EtOAc (3×50mL). The combined EtOAc layer was washed with H₂O (2×50 mL), dried(Na₂SO₄), and concentrated to give 11.7 g (79%) of2-(3-bromophenyl)-2-(tert-butoxycarbonyl) propanoic acid as a whitesolid. ¹H NMR (CDCl₃) δ 7.61 (s, 1H), 7.41 (m, 2H), 7.24 (m, 1H), 1.98(s, 3H), 1.44 (s, 9H).

To a solution of 2-(3-bromophenyl)-2-(tert-butoxycarbonyl) propanoicacid (11.3 g, 32.8 mmol) in MeOH (35 mL) was added toluene (175 mL)followed by TMSCHN₂ (2M in hexane, 44 mL, 98 mmol, 3 eq). The mixturewas stirred at RT for 16 h. Solvents were evaporated and the residue waschromatographed on silica by eluting with EtOAc/hexanes to give 11.8 g(100%) of methyl 2-(3-bromophenyl)-2-(tert-butoxycarbonyl)propanoate asa yellow oil. ¹H NMR (CDCl₃) δ 7.59 (t, J=1.8 Hz, 1H), 7.36-7.44 (m,2H), 7.21 (t, J=8.0 Hz, 1H), 5.92 (s, 1H), 3.70 (s, 3H), 1.97 (s, 3H),1.36 (br s, 9H).

To a solution of methyl 2-(3-bromophenyl)-2-(tert-butoxycarbonyl)propanoate (11.8 g, 33 mmol) in THF (150 mL) at −78° C. was added LAHpowder (3.1 g, 82.0 mmol, 2.5 eq). The mixture was stirred at −78° C.and allowed to warm to RT over 16 h. The mixture was cooled to 0° C. andthe reaction was quenched by slowly adding 3 mL of H₂O. The mixture wasdiluted with DCM (500 mL) followed by the addition of 1N NaOH (6 mL) andH₂O (9 mL). After stirring at 0° C. for 30 min, the mixture was filteredand the filtrate was concentrated to give 10 g (95%) of tert-butyl2-(3-bromophenyl)-1-hydroxypropan-2-ylcarbamate (DC3; R⁶=Me) as acolorless oil. ¹H NMR (CDCl₃) δ 7.49 (t, J=1.8 Hz, 1H), 7.35-7.39 (m,1H), 7.27-7.30 (m, 1H), 7.21 (t, J=7.8 Hz, 1H), 3.72 (m, 2H), 1.57 (s,3H), 1.41 (br s, 9H).

Method DC, Step 4;3-(tert-Butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide

To a solution of SOCl₂ (5.7 mL, 2.5 eq) in dry CH₃CN (37 mL) under argonwas cooled to −40° C. was added tert-butyl2-(3-bromophenyl)-1-hydroxypropan-2-ylcarbamate (DC3; R⁴=Me) (10.3 g, 31mmol) in dry CH₃CN (27 mL) was added dropwise, followed by the additionof dry pyridine (12.4 mL, 160 mmol, 5 eq). The mixture was then allowedto warm to RT in 1 h. The mixture was concentrated to about 30 mL. EtOAc(30 mL) was added and the precipitate was filtered off. The filtrate wasconcentrated in vacuo to give 10.4 g (89%) of3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2-oxideas a colorless oil. ¹H NMR (CDCl₃) δ 7.64 (t, J=2.0 Hz, 1H), 7.36-7.53(m, 2H), 7.24 (m, 1H), 4.52 (q, J=9.5 Hz, 2H), 1.86 (s, 3H), 1.42 (br s,9H).

To a solution of3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2-oxide(10.4 g, 28 mmol) in CH₃CN (50 mL) at 0° C. was added RuO₄ (0.5% instabilized aq., 50 mg, 0.1% by weight) in H₂O (10 mL) amd NalO₄ (8.9 g,41.5 mmol, 1.5 eq) in H₂O (35 mL). The mixture was stirred at RT for 2h. The mixture was partitioned between Et₂O (200 mL) and H₂O (50 mL).The organic layer was separated and the aqueous layer was extracted withEt₂O (3×50 mL). The combined organic layer was dried (Na₂SO₄), andconcentrated to give 10.8 g (100%) of3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide(DC4; R⁶=Me) as a white solid (−10.8 g, yield: 100%). ¹H NMR (CDCl₃) S7.56 (t, J=1.8 Hz, 1H), 7.48-7.52 (m, 1H), 7.38-7.44 (m, 1H), 7.30 (t,J=8.0 Hz, 1H), 4.41 (dd, J1=9.3 Hz, J2=20.4 Hz, 2H), 2.01 (s, 3H), 1.39(s, 9H).

Method DC, Step 5;3-Allyl-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide

3-(tert-Butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide(DC4; R⁶=Me) (10.8 g, 28 mmol) was dissolved in 25% TFA in DCM (40 mL, 5eq) and the mixture was left standing at RT for 3 h. The mixture wasconcentrated in vacuo to give 7.3 g (91%) of4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide as ayellow oil. ¹H NMR (CDCl₃) δ 7.59 (t, J=1.8 Hz, 1H), 7.48-7.52 (m, 1H),7.39-7.42 (m, 1H), 7.30 (t, J=8.1 Hz, 1H), 4.59 (m, 2H), 1.82 (s, 3H).

To a solution of4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (7.3 g,25 mmol) in DCM (77 mL) was added allyl iodide (9.1 mL, 100 mmol, 4 eq),followed by BnBu₃NCl (0.39 g, 1.3 mmol) and 40% NaOH (28 mL). Themixture was stirred at RT for 16 h. The organic layer was separated andthe solvent was evaporated. Silica gel chromatography using 5-20%EtOAc/hexanes gave 8.3 g (100%) of3-allyl-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide(DC5; R⁶=Me) as a colorless oil. ¹H NMR (CDCl₃) δ 7.64 (t, J=1.8 Hz,1H), 7.46-7.54 (m, 2H), 7.31 (t, J=8.0 Hz, 1H), 5.77-5.89 (m, 1H),5.19-5.33 (m, 2H), 4.38 (dd, J1=8.7 Hz, J2=23.7 Hz, 2H), 3.46-3.68 (m,2H), 1.83 (s, 3H).

Method DC, Step 6; N-(2-(3-bromophenyl)-2-amino)prop-1-oxy)-methylamine

To a suspension of NaH (60%, 0.14 g, 1.5 eq) in 0.5 mL of anhydrous DMFwas added tert-butyl hydroxy(methyl)carbamate (0.52 g, 1.5 eq) in 1.5 mLof DMF. After stirring at RT for 15 min, a solution of3-allyl-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide(DC5; R⁶=Me) (0.78 g, 2.3 mmol) in 6 mL of anhydrous DMF was addeddropwise. The mixture was stirred at RT for 16 h. The mixture waspartitioned between EtOAc (10 mL) and 1N HCl (3 mL). The organic layerwas separated and the aqueous layer was extracted with EtOAc (3×5 mL).The combined organic layer was dried over Na₂SO₄ and concentrated togive 0.45 g (41%) of a product which was used without purification.

To a solution of the above product (3.86 g, 8.1 mmol) in THF (30 mL) wasadded a pre-stirred (15 min) mixture of Pd₂(dba)₃ (0.51 g, 0.41 mmol)and 1,4-bis(diphenylphosphio)butane (0.25 g, 0.41 mmol) in THF (5 mL),followed by thiosalicyliacid (2.2 g, 1.2 eq). The mixture was stirred atRT for 16 h. Solvent was evaporated and the residue was chromatographedon silica by eluting with 50% EtOAc/hexanes to give 1.3 g (37%) productas a oil which was dissolved in 4M HCl/dioxane (11 mL) and the mixturewas stirred at RT for 2 h. Solvent was evaporated in vacuo and theresidue was diluted with CHCl₃ (10 mL) followed by treatment with 1NNaOH tol pH ˜12. The organic layer was separated and the aqueous layerwas extracted with CHCl₃ (3×10 mL). The combined organic layer was dried(Na₂SO₄) and concentrated to give 0.56 g (76%) ofN-(2-(3-bromophenyl)-2-amino)prop-1-oxy)-methylamine (DC6; R⁶=Me, R¹=Me)as a colorless oil. ¹H NMR (CDCl₃) δ 7.74 (t, J=1.8 Hz, 1H), 7.41-7.50(m, 2H), 7.26 (t, J=8.0 Hz, 1H), 3.85 (dd, J1=9.6 Hz, J2=28.8 Hz, 2H),2.72 (s, 3H), 1.48 (s, 3H).

Method DC, Step 7;5-(3-Bromophenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

To a solution of N-(2-(3-bromophenyl)-2-amino)prop-1-oxy)-methylamine(DC6; R⁶=Me, R¹=Me) (0.76 g, 2.9 mmol) in EtOH (10 mL) was added BrCN(0.46 g, 4.4 mmol, 1.5 eq). After stirring at RT for 16 h, the mixturewas concentrated. The residue was redissolved in CHCl₃ (20 mL) andwashed with 2N NaOH (10 mL). The aqueous layer was extracted with CHCl₃(3×10 mL). The combined organic layer was dried over Na₂SO₄ andconcentrated to give 0.82 g (100%) of5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine (DC7; R⁶=Me,R¹=Me) as a light yellow oil. ¹H NMR (CDCl₃) δ 10.59 (S, 1H), 8.12 (brs,1H), 7.46 (m, 2H), 7.29 (m, 2H), 4.14 (dd, J1=11.5 Hz, J2=57.7 Hz, 2H),3.39 (s, 3H), 1.69 (s, 3H).

Method DC, Step 8;5-(3-(3-Cyanophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

A mixture of 5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine(DC7; R⁶=Me, R¹=Me) (0.025 g, 0.088 mmol, 1 eq), 3-cyanophenylboronicacid (0.019 g, 0.13 mmol, 1.5 eq), FibreCat (40 mg), anhydrous ethanol(1.5 mL), and a 1N K₂CO₃ aqueous solution (0.12 mL, 0.12 mmol, 1.4 eq)in a microwave vial was heated in a microwave reactor (Emrys Optimizer)at 110° C. for 15 min. The mixture was filtered, concentrated andpurified by prep HPLC (B) to give 0.012 g (44%) of5-(3-(3-cyanophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine (DC8;R⁶=Me, R¹=Me, R²¹=3-cyanophenyl) as a white solid. ¹H NMR (CDCl₃) δ10.67 (s, 1H), 8.05 (br s, 1H), 7.85 (m, 2H), 7.50-7.66 (m, 5H), 7.35(m, 1H), 4.22 (dd, J1=11.8 Hz, J2=48.6 Hz, 2H), 3.40 (s, 3H), 1.76 (s,3H). MS m/e 307.3 (M⁺H)

Using a similar procedure, the following compounds were also prepared:

5-(3-(3-Pyridyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) 10.85 (s, 1H), 9.13 (s, 1H), 8.76 (m, 1H), 8.65 (m, 1H),7.92 (m, 2H), 7.81 (s, 1H), 7.60 (m, 2H), 7.44 (m, 1H), 4.26 (dd,J1=11.8 Hz, J2=37.4 Hz, 2H), 3.41 (s, 3H), 1.77 (s, 3H). MS m/e 283.2(M⁺H)

5-(3-(5-Pyrimidyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.77 (br s, 1H), 10.42 (s, 1H), 9.26 (s, 1H), 9.07 (s,1H), 7.84 (br s, 1H), 7.57-7.63 (m, 3H), 7.46 (m, 1H), 4.23 (dd, J1=11.5Hz, J2=45.9 Hz, 2H), 3.41 (s, 3H), 1.77 (s, 3H). MS m/e 284.2 (M⁺H)

5-(3-(3-Chlorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.63 (s, 1H), 8.00 (br S, 1H), 7.46-7.55 (m, 5H),7.31-7.7.40 (m, 3H), 4.20 (dd, J1=11.5 Hz, J2=54.4 Hz, 2H), 3.39 (s,3H), 1.76 (s, 3H). MS m/e 316.2 (M⁺H)

5-(3-(3-Trifluoromethoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.72 (s, 1H), 8.03 (br s, 1H), 7.55 (m, 1H), 7.51 (m,2H), 7.46 (m, 2H), 7.41 (m, 1H), 7.32-7.34 (dt, J1=1.6 Hz, J2=7.2 Hz,1H), 7.21-7.23 (m, 1H), 4.21 (dd, J1=11.8 Hz, J2=53.0 Hz, 2H), 3.39 (s,3H), 1.76 (s, 3H). MS m/e 366.2 (M⁺H)

5-(3-(3-Toluyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.61 (s, 1H), 8.07 (br s, 1H), 7.53 (m, 2H), 7.45 (m,1H), 7.33-7.37 (m, 3H), 7.28-7.32 (m, 1H), 7.17-7.19 (m, 1H), 4.20 (dd,J1=11.8 Hz, J2=58.2 Hz, 2H), 3.38 (s, 3H), 2.42 (s, 3H), 1.76 (s, 3H).MS m/e 296.4 (M⁺H)

5-(3-(3,5-Dichlorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) 810.71 (s, 1H), 8.06 (br s, 1H), 7.47 (m, 3H), 7.43 (m,2H), 7.35 (m, 2H), 4.20 (dd, J1=11.7 Hz, J2=54.9 Hz, 2H), 3.40 (s, 3H),1.76 (s, 3H). MS m/e 350.2 (M⁺H)

5-(3-(2-Fluoro-5-cyanophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) 610.50 (s, 1H), 7.86 (br s, 1H), 7.77 (dd, J1=2.1 Hz,J2=6.9 Hz, 1H), 7.65 (m, 1H), 7.50 (m, 2H), 7.42 (m, 1H), 7.27 (t, J=5.0Hz, 2H), 4.20 (dd, J1=12.0 Hz, J2=50.4 Hz, 2H), 3.40 (s, 3H), 1.76 (s,3H). MS m/e 325.1 (M⁺H)

5-(3-(2-Fluoro-5-methoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) 10.53 (s, 1H), 7.94 (brs, 1H), 7.47 (m, 3H), 7.37 (m,1H), 7.07 (t, J=9.5 Hz, 1H), 6.93 (m, 1H), 6.86 (m, 1H), 4.19 (dd,J1=11.7 Hz, J2=58.5 Hz, 2H), 3.82 (s, 3H), 3.38 (s, 3H), 1.75 (s, 3H).MS m/e 330.1 (M⁺H)

5-(3-(3-Dimethylaminocarbonylphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) 10.58 (s, 1H), 7.95 (brs, 1H), 7.26-7.65 (m, 8H), 4.20(dd, J1=11.5 Hz, J2=54.7 Hz, 2H), 3.38 (s, 3H), 3.14 (s, 3H), 3.02 (s,3H), 1.75 (s, 3H). MS m/e 353.2 (M⁺H)

5-(3-(2,5-Dimethoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.50 (s, 1H), 7.99 (brs, 1H), 7.40-7.50 (m, 3H),7.29-7.33 (m, 1H), 6.84-6.94 (m, 3H), 4.18 (dd, J1=11.5 Hz, J2=65.4 Hz,2H), 3.80 (s, 3H), 3.74 (s, 3H), 3.37 (s, 3H), 1.74 (s, 3H). MS m/e342.2 (M⁺H)

5-(3-(3-Hydroxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 9.75 (s, 1H), 7.39-7.54 (m, 3H), 7.21-7.30 (m, 2H),7.10-7.12 (m, 2H), 6.82-6.84 (m, 1H), 5.83 (br s, 2H), 4.15 (dd, J1=11.5Hz, J2=35.7 Hz, 2H), 3.36 (s, 3H), 1.74 (s, 3H). MS m/e 298.3 (M⁺H)

5-(3-(3-Fluorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) 810.77 (s, 1H), 8.15 (s, 1H), 7.25-7.56 (m, 7H),7.01-7.08 (m, 1H), 4.20 (dd, J1=11.5 Hz, J2=53.0 Hz, 2H), 3.40 (s, 3H),1.76 (s, 3H). MS m/e 300.2 (M⁺H)

5-(3-(4-Cyanophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.67 (s, 1H), 8.01 (br s, 1H), 7.74 (s, 4H), 7.63 (s,1H), 7.48-7.56 (m, 2H), 7.33-7.35 (m, 1H), 4.23 (dd, J1=11.5 Hz, J2=47.2Hz, 2H), 3.40 (s, 3H), 1.76 (s, 3H). MS m/e 307.2 (M⁺H)

5-(3-(4-Methoxy-3-pyridyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) & 10.55 (s, 1H), 8.74 (d, J=6.0 Hz, 1H), 8.64 (s, 1H),7.83 (br s, 1H), 7.49-7.53 (m, 3H), 7.37-7.42 (m, 2H), 4.20 (dd, J1=11.5Hz, J2=49.4 Hz, 2H), 4.11 (s, 3H), 3.39 (s, 3H), 1.76 (s, 3H). MS m/e313.2 (M⁺H)

Method DD, Step 1;

To a 10 mL MeOH solution of DD1 (R³=R⁶=H. R⁷=Me, 1 g) was addedp-methoxybenzaldehyde (1 eq) and 4 A molecular sieves (4 g). Thesolution was stirred overnight before sodium borohydride (1 eq) wasadded and reaction stirred for 1 h. The reaction mixture was filted andsolvent evaporated. The residue was chromatographed using MeOH/DCM toafford compound DD2 (R³=R⁶=H, R⁷=Me).

Method DD, Step 2;

Procedure similar to Method CF, step 2 was used for generation of DD3(R¹=Me, R³=R⁶=H. R⁷=Me,).

Method DD, Step 3;

Procedure similar to Method CF, step 3 was used for generation of DD4(R¹=Me, R³=R⁶=H, R⁷=Me) from DD3

Method DD, Step 4;

Compound DD4 was hydrogenated using Pd(OH)₂/C in Methanol. After removalof the catalyst and solvent the crude product was treated with 20% TFAin DCM to give product DD5 (R¹=Me, R³=R⁶=H R⁷=Me) after purification.

Method DE, Step 1:5-(4-Chlorophenyl)-3-methylsulfanyl-5,6-dihydro-4H-[1,2,4]thiadiazine1,1-dioxide

2-(4-Chlorophenyl)ethenesulfonyl chloride DE1 is treated with 1.2equivalents of S-methyl isothiourea hemisulfate and a slight excess of1N NaOH in acetone. After 12 h at RT the mixture is concentrated invacuo and the precipitate collected to give the title compound.

Method DE, Step 2:N-(2-(4-Chlorophenyl)ethene-1-sulfonyl)-S-methylisothiourea

Using a method similar to that described by K. Hasegawa and S. Hirooka(Bull. Chem. Soc. Jap., 1972, 45, 1893),N-(2-(4-clorophenyl)ethylene-1-sulfonyl)thiourea DE2 in DMF is treatedwith 1N NaOH (2.4 equivalents) and dimethyl sulfate (1.2 equivalents) at0-10° C. After 3 h at RT, the reaction mixture is poured into ice water.The precipitate is collected, washed with water and dried to give thetitle compound DE3.

Method DE, Step 2:5-(4-Chlorophenyl)-1,1-dioxo-[1,2,4]thiadiazinan-3-one

Using a method similar to that described by K. Hasegawa and S. Hirooka(Bull. Chem. Soc. Jap., 1972, 45, 1893),5-(4-chlorophenyl)-3-methylsulfanyl-5,6-dihydro-4H-[1,2,4]thiadiazine1,1-dioxide DE2 in acetone is treated with 1N NaOH and the mixture isrefluxed for 2 h. The acetone is evaporated and the mixture is acidifiedwith conc. HCl to afford the title compound DE3.

Method DE, Step 3:5-(4-Chlorophenyl)-2-methyl-1,1-dioxo-[1,2,4]thiadiazinan-3-one

Using a method similar to that described by A. Etienne et al. (Bull.Soc. Chim. Fr., 1974, 1395)5-(4-chlorophenyl)-1,1-dioxo-[1,2,4]thiadiazinan-3-one DE3 is treatedwith sodium methoxide (1 equivalent) in methanol. Add methyl iodide (1.2equivalent) in DMF and allow to stir for 12 h. Pour the mixture into icewater and collect the precipitate of the title compound DE4.

Method DE, Step 4:5-(4-Chlorophenyl)-2-methyl-1,1-dioxo-[1,2,4]thiadiazinan-3-thione

To a solution of DE4 in toluene (or xylene) is added Lawesson's reagent(1.2 equivalents), and the mixture is stirred at reflux for 2 h. Themixture is cooled and poured into cold water. The organic phase is dried(MgSO₄) and filtered, and solvent is removed. The crude product ispurified by flash chromatography to provide the title compound (DE5).

Method DE, Step 5:5-(4-Chlorophenyl)-2-methyl-1,1-dioxo-[1,2,4]thiadiazinan-3-ylideneamine

Using a route similar to that described in Method A, step 3, DE5 is usedto prepare the title compound (DE6).

As a variant of this method, DE2 is treated with ammonia and theresultant product is treated with sodium hydride and methyl iodide inDMF to give the product DE6

Method DF, Step 1: 2-Hydrazinocarbonylpropane-2-sulfonic acidcyclohexylamide

Using a method similar to that described by S. Paik and E. H. White(Tetrahedron, 1996, 52, 5303), 2-cyclohexylsulfamoyl-2-methylpropionicacid ethyl ester DF1 (which is prepared by the method of A. De Blic etal. (Synthesis, 1982, 281)) in ethanol is treated with 1.2 equivalent of95% hydrazine under N₂ and the mixture is allowed to stand at RT for 12h. The reaction mixture is concentrated to give the title compound DF2which is used directly in Step 2.

Method DF, Step 2:2-Cyclohexyl-5,5-dimethyl-1,2,4-thiadiazolidin-3-one-1,1-dioxide

A solution of DF2 in CH₂Cl₂ is refluxed under a N₂ for 10 h. The solventis removed in vacuo and the crude product is purified by flashchromatography to provide the title compound DF3.

Method DF, Step 3:2-Cyclohexyl-5,5-dimethyl-1,2,4-thiadiazolidin-3-thione-1,1-dioxide

To a solution of DF3 in toluene (or xylene) is added Lawesson's reagent(1.2 equivalents), and the mixture is stirred at reflux for 2 h. Themixture is cooled and poured into cold water. The organic phase is dried(MgSO₄) and filtered, and solvent is removed. The crude product ispurified by flash chromatography to provide the title compound (DF4).

Method DF, Step 4:2-Cyclohexyl-5,5-dimethyl-1,2,4-thiadiazolidin-3-imine-1,1-dioxide

Using a route similar to that described in Method A, step 3, DF4 is usedto prepare the title compound (DF5).

The following table contains example compounds which were synthesizedwith procedure(s) similar to methods listed in the corresponding columnand whose LCMS data (obs. mass) are also listed. Obs. # Compounds MethodMass 1491

CF 297 1492

CF 333.9 1493

CF 329.9 1494

CF 367.9 1495

AW 281 1496

CF 306 1497

AB 307 1498

CF 314 1499

CF 318 1500

CF 325 1501

CF 325 1502

CF 330 1503

CF 336 1504

CF 336 1505

AB 340 1506

CE 342 1507

CF 343 1508

CF 344 1509

CF 344 1510

CF 344 1511

AB 354 1512

A 354 1513

CF 358 1514

CF 358 1515

BS 358 1516

A 364 1517

A 366 1518

A 366 1519

A 368 1520

A 370 1521

AB 374 1522

A 380 1523

A 382 1524

A 382 1525

BS 383 1526

CF 384 1527

A 384 1528

A 384 1529

A 384 1530

A 384 1531

A 396 1532

A 396 1533

A 397 1534

A 398 1535

A 398 1536

A 398 1537

A 398 1538

A 398 1539

A 400 1540

A 402 1541

AB 404 1542

A 406 1543

A 406 1544

BS 408 1545

A 410 1546

A 410 1547

A 411 1548

A 412 1549

A 412 1550

A 414 1551

CE 415 1552

A 416 1553

A 417 1554

A 417 1555

A 419 1556

A 420 1557

A 421 1558

A 422 1559

A 422 1560

A 422 1561

A 423 1562

A 423 1563

CE 424 1564

A 425 1565

A 426 1566

A 426 1567

A 426 1568

A 431 1569

A 431 1570

A 431 1571

A 433 1572

A 434 1573

A 437 1574

A 439 1575

A 465 1576

CG 470 1577

CG 470 1578

CG 470 1579

CG 470 1580

CE 474 1581

CG 484 1582

CG 484 1583

BR 489 1584

CF 274.1 1585

AW 311.1 1586

AB 312.1 1587

AB 319.1 1588

CF 320.1 1589

CF 325.1 1590

AB 328.1 1591

AW 332.1 1592

CE 333.1 1593

CF 336.1 1594

AW 337.1 1595

CF 337.1 1596

CF 337.1 1597

CF 337.1 1598

AB 338.1 1599

AB 338.1 1600

CE 338.1 1601

CF 339.1 1602

CE 339.1 1603

AB 342.1 1604

AW 343.1 1605

AB 345.1 1606

AB 346.1 1607

AB 350.1 1608

CF 350.1 1609

AW 356.1 1610

AW 357.1 1611

AW 359.1 1612

AB 362.1 1613

CE 364.1 1614

CE 365.1 1615

AW 367.1 1616

AW 368.1 1617

AW 372.1 1618

CF 373.1 1619

AB 378.1 1620

AW 378.1 1621

CF 379.1 1622

CF 384.1 1623

BQ 386.1 1624

BQ 387.1 1625

AB 388.1 1626

CO 399.1 1627

BW 412.1 1628

BW 412.1 1629

CE 414.1 1630

BQ 419.1 1631

AW 421.1 1632

AM 425.1 1633

AW 425.1 1634

BW 426.1 1635

AW 436.1 1636

BO 439.1 1637

BQ 440.1 1638

BQ 453.1 1639

CH 455.1 1640

BW 463.1 1641

Q 468.1 1642

BS 478.1 1643

BS 478.1 1644

BS 484.1 1645

BS 484.1 1646

BQ 492.1 1647

BQ 492.1 1648

BW 495.1 1649

BW 496.1 1650

Q 560.1 1651

AW 569.1 1652

BW 573.1 1653

AW 470.1 1654

AW 307.2 1655

AW 308.2 1656

CP 308.2 1657

AW 315.2 1658

AW 321.2 1659

CO 321.2 1660

AW 325.2 1661

AW 326.2 1662

AW 328.2 1663

AW 331.2 1664

CE 335.2 1665

AW 336.2 1666

AW 337.2 1667

CF 339.2 1668

AW 340.2 1669

CO 341.2 1670

AW 342.2 1671

AW 346.2 1672

AW 350.2 1673

CJ 352.2 1674

AW 354.2 1675

AW 355.2 1676

CE 359.2 1677

AW 361.2 1678

AW 361.2 1679

AW 361.2 1680

AW 362.2 1681

AW 368.2 1682

AW 372.2 1683

AW 374.2 1684

BQ 375.2 1685

CL 377.2 1686

BK 377.2 1687

AW 377.2 1688

CG 378.2 1689

AW 383.2 1690

CO 385.2 1691

BQ 386.2 1692

AW 406.2 1693

CL 408.2 1694

BS 409.2 1695

BW 412.2 1696

BW 413.2 1697

BS 413.2 1698

BS 420.2 1699

R 425.2 1700

R 425.2 1701

BQ 429.2 1702

BQ 430.2 1703

R 434.2 1704

R 434.2 1705

BW 437.2 1706

AW 439.2 1707

BQ 440.2 1708

BQ 441.2 1709

BQ 441.2 1710

BW 442.2 1711

BQ 445.2 1712

BQ 446.2 1713

R 446.2 1714

R 446.2 1715

BS 448.2 1716

R 448.2 1717

BQ 450.2 1718

BQ 450.2 1719

BW 451.2 1720

Cl 452.2 1721

BQ 454.2 1722

BQ 454.2 1723

AW 419.2 1724

AW 423.2 1725

AW 430.2 1726

AW 431.2 1727

AW 435.2 1728

CK 439.2 1729

AW 441.2 1730

AW 450.3 1731

CK 453.3 1732

CK 453.3 1733

AW 453.3 1734

CK 455.3 1735

L 467.3 1736

L 467.3 1737

CK 469.3 1738

CK 481.3 1739

CK 483.3 1740

CK 497.3 1741

CK 525.3 1742

BQ 515.3 1743

BQ 516.3 1744

BQ 519.3 1745

BS 522.3 1746

BQ 525.3 1747

BQ 532.3 1748

CG 576.3 1749

BQ 455.3 1750

BW 456.3 1751

BQ 456.3 1752

BQ 456.3 1753

BS 456.3 1754

BQ 456.3 1755

AW 456.3 1756

BQ 458.3 1757

BQ 458.3 1758

BQ 458.3 1759

BQ 458.3 1760

BS 460.3 1761

R 460.3 1762

BW 462.3 1763

BW 462.3 1764

BW 463.3 1765

BQ 464.3 1766

BQ 464.3 1767

BW 465.3 1768

BQ 467.3 1769

Q 467.3 1770

BS 468.3 1771

BW 468.3 1772

Q 468.3 1773

BQ 469.3 1774

BQ 469.3 1775

CG 469.3 1776

BQ 470.3 1777

BQ 470.3 1778

BS 472.3 1779

BQ 473.3 1780

BQ 473.3 1781

BS 473.3 1782

Q 473.3 1783

AW 473.3 1784

BQ 474.3 1785

BQ 478.3 1786

AZ 478.3 1787

AZ 478.3 1788

BS 479.3 1789

Q 481.3 1790

BS 482.3 1791

Q 482.3 1792

R 482.3 1793

R 482.3 1794

R 482.3 1795

R 482.3 1796

BS 484.3 1797

R 486.3 1798

R 486.3 1799

CK 487.3 1800

BS 488.3 1801

BS 488.3 1802

BS 488.3 1803

BQ 488.3 1804

BW 488.3 1805

R 488.3 1806

BQ 489.3 1807

BQ 489.3 1808

AW 489.3 1809

BQ 492.3 1810

Q 493.3 1811

BS 497.3 1812

CG 497.3 1813

BS 498.3 1814

R 498.3 1815

498.3 1816

498.3 1817

R 500.3 1818

R 502.3 1819

R 502.3 1820

BS 504.3 1821

BS 504.3 1822

BQ 504.3 1823

BQW 508.3 1824

CF 329.1, 331.1 1825

CF 334.0, 336.0 1826

CF 342.1, 344.1 1827

CF 352.0, 353.9 1828

CF 358.1, 360.1 1829

CF 363.1. 365.1 1830

CF 367.9. 369.9 1831

A 501.1 499 1832

CE 309

Human Cathepsin D FRET Assay

This assay can be run in either continuous or endpoint format. Thesubstrate used below has been described (Y. Yasuda et al., J. Biochem.,125, 1137 (1999)). Substrate and enzyme are commercially available.

The assay is run in a 30 ul final volume using a 384 well Nunc blackplate. 8 concentrations of compound are pre-incubated with enzyme for 30mins at 37 C followed by addition of substrate with continued incubationat 37 C for 45 mins. The rate of increase in fluorescence is linear forover 1 h and is measured at the end of the incubation period using aMolecular Devices FLEX station plate reader. Kis are interpolated fromthe IC50s using a Km value of 4 uM and the substrate concentration of2.5 uM.

Reagents

Na-Acetate pH 5

1% Brij-35 from 10% stock (Calbiochem)

DMSO

Purified (>95%) human liver Cathepsin D (Athens Research & TechnologyCat# 16-12-030104)

Peptide substrate (Km=4 uM)Mca-Gly-Lys-Pro-lle-Leu-Phe-Phe-Arg-Leu-Lys(Dnp)-D-Arg-NH₂ Bachem Cat #M-2455

Pepstatin is used as a control inhibitor (Ki˜0.5 nM) and is availablefrom Sigma.

Nunc 384 well black plates

Final Assay Buffer Conditions

100 mM Na Acetate pH 5.0

0.02% Brij-35

1% DMSO

Compound is diluted to 3× final concentration in assay buffer containing3% DMSO. 10 ul of compound is added to 10 ul of 2.25 nM enzyme (3×)diluted in assay buffer without DMSO, mixed briefly, spun, and incubatedat 37 C for 30 mins. 3× substrate (7.5 uM) is prepared in 1× assaybuffer without DMSO. 10 ul of substrate is added to each well mixed andspun briefly to initiate the reaction. Assay plates are incubated at 37C for 45 mins and read on 384 compatible fluorescence plate reader usinga 328 nm Ex and 393 nm Em.

Compounds of the present invention exhibit hCathD Ki data ranges fromabout 0.1 to about 500 nM, preferably about 0.1 to about 100 nM morepreferably about 0.1 to about 75 nM.

The following are examples of compounds that exhibit hCathD Ki dataunder 75 nM.

The following compound

has a hCath D Ki value of 0.45 nM.

BA CE-1 Cloning, Protein Expression and Purification

A predicted soluble form of human BACE1 (sBACE1, corresponding to aminoacids 1-454) was generated from the full length BACE1 cDNA (full lengthhuman BACE1 cDNA in pCDNA4/mycHisA construct; University of Toronto) byPCR using the advantage-GC cDNA PCR kit (Clontech, Palo Alto, Calif.). AHindIII/Pmel fragment from pCDNA4-sBACE1 myc/His was blunt ended usingKlenow and subcloned into the Stu I site of PFASTBACI(A) (Invitrogen). AsBACE1 mycHis recombinant bacmid was generated by transposition inDH10Bac cells (GIBCO/BRL). Subsequently, the sBACE1 mycHis bacmidconstruct was transfected into sf9 cells using CellFectin (Invitrogen,San Diego, Calif.) in order to generate recombinant baculovirus. Sf9cells were grown in SF 900-II medium (Invitrogen) supplemented with 3%heat inactivated FBS and 0.5× penicillin/streptomycin solution(Invitrogen). Five milliliters of high titer plaque purifiedsBACEmyc/His virus was used to infect 1 L of logarithmically growing sf9cells for 72 hours. Intact cells were pelleted by centrifugation at3000×g for 15 minutes. The supernatant, containing secreted sBACE1, wascollected and diluted 50% v/v with 100 mM HEPES, pH 8.0. The dilutedmedium was loaded onto a Q-sepharose column. The Q-sepharose column waswashed with Buffer A (20 mM HEPES, pH 8.0, 50 mM NaCl).

Proteins, were eluted from the Q-sepharose column with Buffer B (20 mMHEPES, pH 8.0, 500 mM NaCl). The protein peaks from the Q-sepharosecolumn were pooled and loaded onto a Ni-NTA agarose column. The Ni-NTAcolumn was then washed with Buffer C (20 mM HEPES, pH 8.0, 500 mM NaCl).Bound proteins were then eluted with Buffer D (Buffer C+250 mMimidazole). Peak protein fractions as determined by the Bradford Assay(Biorad, CA) were concentrated using a Centricon 30 concentrator(Millipore). sBACE1 purity was estimated to be −90% as assessed bySDS-PAGE and Commassie Blue staining. N-terminal sequencing indicatedthat greater than 90% of the purified sBACE1 contained the prodomain;hence this protein is referred to as sproBACE1.

Peptide Hydrolysis Assay

The inhibitor, 25 nM EuK-biotin labeled APPsw substrate(EuK-KTEEISEVNLDAEFRHDKC-biotin; CIS-Bio International, France), 5 μMunlabeled APPsw peptide (KTEEISEVNLDAEFRHDK; American Peptide Company,Sunnyvale, Calif.), 7 nM sproBACE1, 20 mM PIPES pH 5.0, 0.1% Brij-35(protein grade, Calbiochem, San Diego, Calif.), and 10% glycerol werepreincubated for 30 min at 30° C. Reactions were initiated by additionof substrate in a 5 μl aliquot resulting in a total volume of 25 μl.After 3 hr at 30° C. reactions were terminated by addition of an equalvolume of 2× stop buffer containing 50 mM Tris-HCl pH 8.0, 0.5 M KF,0.001% Brij-35, 20 μg/ml SA-XL665 (cross-linked allophycocyanin proteincoupled to streptavidin; CIS-Bio International, France) (0.5 μg/well).Plates were shaken briefly and spun at 1200×g for 10 seconds to pelletall liquid to the bottom of the plate before the incubation. HTRFmeasurements were made on a Packard Discovery® HTRF plate reader using337 nm laser light to excite the sample followed by a 50 μs delay andsimultaneous measurements of both 620 nm and 665 nm emissions for 400μs.

IC₅₀ determinations for inhibitors, (1), were determined by measuringthe percent change of the relative fluorescence at 665 nm divided by therelative fluorescence at 620 nm, (665/620 ratio), in the presence ofvarying concentrations of/and a fixed concentration of enzyme andsubstrate. Nonlinear regression analysis of this data was performedusing GraphPad Prism 3.0 software selecting four parameter logisticequation, that allows for a variable slope.Y=Bottom+(Top-Bottom)/(1+10ˆ((LogEC50-X)*Hill Slope)); X is thelogarithm of concentration of 1, Y is the percent change in ratio and Ystarts at bottom and goes to top with a sigmoid shape.

Compounds of the present invention have an IC₅₀ range from about 0.001to about 500 μM, preferably about 0.001 to about 100 μM, more preferablyabout 0.001 to about 20 μM.

Examples of compounds with human BACE 1 IC50<1 μM are listed below:

Human Mature Renin Enzyme Assay:

Human Renin was cloned from a human kidney cDNA library and C-terminallyepitope-tagged with the V5-6His sequence into pCDNA3.1.pCNDA3.1-Renin-V5-6His was stably expressed in HEK293 cells and purifiedto >80% using standard Ni-Affinity chromatography. The prodomain of therecombinant human renin-V5-6His was removed by limited proteolysis usingimmobilized TPCK-trypsin to give mature-human renin. Renin enzymaticactivity was monitored using a commercially available fluorescenceresonance energy transfer (FRET) peptide substrate, RS-1 (MolecularProbes, Eugene, Oreg.) in 50 mM Tris-HCl pH 8.0, 100 mM NaCl, 0.1%Brij-35 and 5% DMSO buffer for 40 mins at 30 degrees celsius in thepresence or absence of different concentrations of test compounds.Mature human Renin was present at approximately 200 nM. Inhibitoryactivity was defined as the percent decrease in renin inducedfluorescence at the end of the 40 min incubation compared to vehiclecontrols and samples lacking enzyme. Compound 1% of hRenin at 100 μM

68.8

75.3

76.9

In the aspect of the invention relating to a combination of at least onecompound of formula I with at least one cholinesterase inhibitor,acetyl- and/or butyrylchlolinesterase inhibitors can be used. Examplesof cholinesterase inhibitors are tacrine, donepezil, rivastigmine,galantamine, pyridostigmine and neostigmine, with tacrine, donepezil,rivastigmine and galantamine being preferred. Preferably, thesecombinations are directed to the treatment of Alzheimer's disease.

In the aspect of the invention relating to a combination of at least onecompound of formula I with at least one muscarinic m₁ agonist or m₂antagonist can be used. Examples of m₁ agonists are known in the art.Examples of m₂ antagonists are also known in the art; in particular, m₂antagonists are disclosed in U.S. Pat. Nos. 5,883,096; 6,037,352;5,889,006; 6,043,255; 5,952,349; 5,935,958; 6,066,636; 5,977,138;6,294,554; 6,043,255; and 6,458,812; and in WO 03/031412, all of whichare incorporated herein by reference.

In other aspects of the invention relating to a combination of at leastone compound of formula I and at least one other agent, for example abeta secretase inhibitor; a gamma secretase inhibitor; an HMG-CoAreductase inhibitor such as atorvastatin, lovastatin, simvistatin,pravastatin, fluvastatin and rosuvastatin; non-steroidalanti-inflammatory agents such as, but not necessarily limited toibuprofen, relafen or naproxen; N-methyl-D-aspartate receptorantagonists such as memantine; anti-amyloid antibodies includinghumanized monoclonal antibodies; vitamin E; nicotinic acetylcholinereceptor agonists; CB1 receptor inverse agonists or CB1 receptorantagonists; antibiotics such as doxycycline; growth hormonesecretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors;GABAA inverse agonists; inhibitors of amyloid aggregation; glycogensynthase kinase beta inhibitors; promoters of alpha secretase activity.Preferably, these combinations are directed to the treatment ofAlzheimer's disease.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 300 mg/day, preferably 1 mg/day to 50 mg/day, in two tofour divided doses.

When a compound of formula I is used in combination with acholinesterase inhibitor to treat cognitive disorders, these two activecomponents may be co-administered simultaneously or sequentially, or asingle pharmaceutical composition comprising a compound of formula I anda cholinesterase inhibitor in a pharmaceutically acceptable carrier canbe administered. The components of the combination can be administeredindividually or together in any conventional oral or parenteral dosageform such as capsule, tablet, powder, cachet, suspension, solution,suppository, nasal spray, etc. The dosage of the cholinesteraseinhibitor can be determined from published material, and may range from0.001 to 100 mg/kg body weight.

When separate pharmaceutical compositions of a compound of formula I anda cholinesterase inhibitor are to be administered, they can be providedin a kit comprising in a single package, one container comprising acompound of formula I in a pharmaceutically acceptable carrier, and aseparate container comprising a cholinesterase inhibitor in apharmaceutically acceptable carrier, with the compound of formula I andthe cholinesterase inhibitor being present in amounts such that thecombination is therapeutically effective. A kit is advantageous foradministering a combination when, for example, the components must beadministered at different time intervals or when they are in differentdosage forms.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A compound selected from the group consisting of


2. A pharmaceutical composition comprising an effective amount of acompound of claim 1 and a pharmaceutically effective carrier.
 3. Amethod of inhibiting aspartyl protease comprising administering to apatient in need of such treatment an effective amount of a compound ofclaim
 1. 4. A method of treating cardiovascular diseases, cognitive andneurodegenerative diseases, and the methods of inhibiting of HumanImmunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymescomprising administering to a patient in need of such treatment aneffective amount of a compound of claim
 1. 5. The method of claim 4wherein a cognitive or neurodegenerative disease is treated.
 6. Themethod of claim 5 wherein Alzheimer's disease is treated.
 7. Apharmaceutical composition comprising an effective amount of a compoundof claim 1, and an effective amount of a cholinesterase inhibitor or amuscarinic m₁ agonist or m₂ antagonist in a pharmaceutically effectivecarrier.
 8. A method of treating a cognitive or neurodegenerativedisease comprising administering to a patient in need of such treatmentan effective amount of a compound of claim 1 in combination with aneffective amount of a cholinesterase inhibitor.
 9. The method of claim 8wherein Alzheimer's disease is treated.
 10. A method of treating acognitive or neurodegenerative disease comprising administering to apatient in need of such treatment an effective amount of a compound ofclaim 1 in combination with an effective amount of a gamma secretaseinhibitor, an HMG-CoA reductase inhibitor or non-steroidalanti-inflammatory agent.
 11. The method of claim 10 wherein Alzheimer'sdisease is treated.
 12. The method of claim 10 wherein said HMG-CoAreductase inhibitor is atorvastatin, lovastatin, simvistatin,pravastatin, fluvastatin or rosuvastatin.
 13. The method of claim 10wherein said non-steroidal anti-inflammatory agent is ibuprofen, relafenor naproxen.
 14. A pharmaceutical composition comprising an effectiveamount of a compound of claim 1, and an effective amount of a gammasecretase inhibitor; an HMG-CoA reductase inhibitor or a non-steroidalanti-inflammatory agent.
 15. A method of treating a cognitive orneurodegenerative disease comprising administering to a patient in needof such treatment an effective amount of at least one compound of claim1 in combination with an effective amount of one or more compoundsselected from the group consisting of a cholinesterase inhibitor,muscarinic m₁ agonist or m₂ antagonist, gamma secretase inhibitor, anHMG-CoA reductase inhibitor and non-steroidal anti-inflammatory agent.